Ventilation Scintigraphy With Radiolabeled Carbon Nanoparticulate Aerosol (Technegas): State-of-the-Art Review and Diagnostic Applications to Pulmonary Embolism During COVID-19 Pandemic.

ABSTRACT: Invented and first approved for clinical use in Australia 36 years ago, Technegas is the technology that enabled ventilation scintigraphy with 99m Tc-labeled carbon nanoparticles ( 99m Tc-CNP). The US Food and Drug Administration (FDA) has considered this technology for more than 30 years but only now is getting close to approving it. Meanwhile, more than 4.4 million patients benefited from this technology in 64 countries worldwide. The primary application of 99m Tc-CNP ventilation imaging is the diagnostic evaluation for suspicion of pulmonary embolism using ventilation-perfusion quotient (V/Q) imaging. Because of 99m Tc-CNP's long pulmonary residence, tomographic imaging emerged as the preferred V/Q methodology. The FDA-approved ventilation imaging agents are primarily suitable for planar imaging, which is less sensitive. After the FDA approval of Technegas, the US practice will likely shift to tomographic V/Q. The 99m Tc-CNP use is of particular interest in the COVID-19 pandemic because it offers an option of a dry radioaerosol that takes approximately only 3 to 5 tidal breaths, allowing the shortest exposure to and contact with possibly infected patients. Indeed, countries where 99m Tc-CNP was approved for clinical use continued using it throughout the COVID-19 pandemic without known negative viral transmission consequences. Conversely, the ventilation imaging was halted in most US facilities from the beginning of the pandemic. This review is intended to familiarize the US clinical nuclear medicine community with the basic science of 99m Tc-CNP ventilation imaging and its clinical applications, including common artifacts and interpretation criteria for tomographic V/Q imaging for pulmonary embolism.

Beneficial effects of dynamic groundwater flow and redox conditions on Natural Attenuation of mono-, poly-, and NSO-heterocyclic hydrocarbons.

Natural Attenuation (NA) processes have been demonstrated to reduce pollutant loads at different contaminated groundwater sites world-wide and are increasingly considered in contaminated site management concepts. However, data are mainly available for steady state groundwater flow and stable redox conditions as well as pollutants listed in standard regulatory schemes. In this study, the influence of transient groundwater flow and redox conditions on NA was examined at a former gas works site near the river Rhine in Germany. The investigated 78 pollutants included 40 mono- and polyaromatic hydrocarbons (MAHs, PAHs) and 38 NSO-heterocyclic aromatic hydrocarbons (NSO-HET). In the highly polluted areas, the MAHs benzene, indene and indane, the PAHs naphthalene, acenaphthene, 1- and 2-methylnaphthalene and the NSO-HET 2-methylquinoline, carbazole, benzothiophene, dibenzofuran and benzofuran were predominant. Pollutant concentrations decreased with increasing distance from the sources of contamination. At the plume fringes, the MAHs benzene and indane, the PAH acenaphthene, the NSO-HET carbazole, 5-methylbenzothiophene, 2- and 3-methylbenzofuran and 2-methyldibenzofuran were predominant, indicating low retention and slow intrinsic biodegradation of these compounds. The influence of surface water on groundwater level, pollutant concentrations, and redox conditions in the monitoring wells was observed with a permanently installed groundwater sensor. The temporary availability of oxygen was observed at the plume fringes, resulting in aerobic and ferric iron reducing biodegradation processes. Field and laboratory data were used to set-up a groundwater flow and reactive transport model used for quantification of the field mass transfer rates. In conclusion, the study demonstrates that NA is effective under transient flow and redox conditions. A conceptual model and reactive transport simulation can facilitate the interpretation of pronounced fluctuations of pollutant concentration in monitoring wells. Based on the analysis of 78 pollutants, indane, indene and several NSO-HET like carbazole, benzothiophene and 2-methyldibenzofuran are recommended for monitoring at tar oil polluted sites, besides EPA-PAHs and BTEX.

Myocardial Perfusion SPECT 2018 in Germany: Results of the 8th Survey.

AIM: This paper presents the results of the 8th survey of myocardial perfusion SPECT (MPS) from the reporting year 2018. METHODS: 291 questionnaires (184 practices (PR), 77 hospitals (HO), 30 university hospitals (UH)) were evaluated. Results of the last survey from 2015 are set in squared brackets. RESULTS: MPS of 145 930 [121 939] patients were reported (+ 19.6 %). 76 % [78 %] of all patients were studied in PR, 16 % [14 %] in HO, and 8 % [8 %] in UH, mostly with a 2-day-protocol 48 % [50 %]. 99.96 % [98 %] of all MPS were performed with Tc-99 m radiopharmaceuticals and in 0.04 % with Tl-201.A pharmacological stress test was applied in 49 % [43 %] (23 % [22 %] adenosine, 26 % [20 %] regadenoson, dipyridamole or dobutamine together < 1 % [1 %]). Attenuation correction was performed in 26 % [25 %] of all MPS, gated SPECT in 86 % [80 %] of stress MPS, in 87 % [78 %] of rest and in 83 % [76 %] of all stress and rest MPS. 67 % [53 %] of the departments performed MPS scoring by default, whereas 16 % [24 %] did not apply this feature at all.69 % [60 %] reported an increase or no changes in their MPS patient numbers. One hundred twenty-six departments which participated in the surveys from 2009 to 2018 reported an increase in MPS by 44 %. 69 % [70 %] of the MPS were requested by ambulatory care cardiologists. CONCLUSION: The 2018 MPS survey reveals a high-grade adherence of routine MPS practice to current guidelines. The positive development in MPS performance and MPS numbers observed since 2012 remains ongoing.

Effects of different progestins on prostaglandin biosynthesis in human endometrial explants.

OBJECTIVE: To compare the effects of chlormadinone acetate (CMA), dienogest (DNG) and drospirenone (DRSP) on prostaglandin biosynthesis in a human endometrial explants model. STUDY DESIGN: Human endometrial explants obtained by aspiration curettage and human endometrial YHES cells were stimulated with interleukin-1ß (IL-1ß) and exposed to CMA, DNG, DRSP or dexamethasone (DEX; YHES cells). Cellular messenger RNA (mRNA) levels of cyclooxygenase-2 (COX-2) were analyzed by reverse-transcription quantitative real-time polymerase chain reaction. Concentrations of prostaglandin F2α (PGF2α) in culture supernatants were measured by enzyme-linked immunosorbent assay. RESULTS: CMA exerted after IL-1ß stimulation a stronger down-regulation of COX-2 mRNA compared to DNG and DRSP in human explants (-55% vs. -40% and 46%, respectively). The effect of CMA on COX-2 mRNA was significantly stronger (p=.025) than that of DNG. Moreover, the effect of CMA was independent from cycle phase or presence of endometriosis. In order to evaluate the impact of the investigated progestins on effector molecules, PGF2α release was determined in supernatants. Again, CMA reduced the PGF2α release significantly by an average of -60% (p<.01). In contrast, no significant reduction was found for DNG and DRSP. In YHES cells, only DEX but not the progestins under study exerted a significant down-regulating effect (-79%, p<.01) on COX-2 mRNA after IL-1ß stimulation. CONCLUSION: Among the tested progestins, CMA displayed the most consistent suppression of prostaglandin biosynthesis in human endometrial explants. IMPLICATION: Among three tested progestins, chlormadinone acetate had the most consistent suppressive effect on prostaglandins in endometrial explants. These findings support clinical observations about the efficacy of chlormadinone acetate in dysmenorrhea treatment.

[Policy paper nuclear cardiology - update 2018 - Current status of clinical practice]. / Positionspapier Nuklearkardiologie ­ Update 2018.

The joint position paper of the working community "Cardiovascular Nuclear Medicine" of the German Society of Nuclear Medicine (DGN) and the working group "Nuclear Cardiology Diagnostics" of the German Cardiac Society (DKG) updates the former 2009 paper. It is the purpose of this paper to provide an overview about the application fields, the state-of-the-art and the current value of nuclear cardiology imaging. The topics covered are chronic coronary artery disease, including viability imaging, furthermore cardiomyopathies, infective endocarditis, cardiac sarcoidosis and amyloidosis.

[Myokard-Perfusions-SPECT. Myocardial perfusion SPECT - Update S1 guideline]. / Myokard-Perfusions-SPECT. Update S1-Leitlinie1.

The S1 guideline for myocardial perfusion SPECT has been published by the Association of the Scientific Medical Societies in Germany (AWMF) and is valid until 2/2022. This paper is a short summary with comments on all chapters and subchapters wich were modified and amended.

Normal human immune cells are sensitive to telomerase inhibition by Brassica-derived 3,3-diindolylmethane,partly mediated via ERα/ß-AP1 signaling.

SCOPE: Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) from Brassica plants are regarded as promising anticancer phytochemicals. The enzyme telomerase is a very attractive target for cancer therapeutics; in normal cells such as lymphocytes, it plays a decisive role for cell maintenance. The effect of I3C and DIM on telomerase in normal human immune cells (PBMC) was studied compared to leukaemia cells (HL-60). Signalling of telomerase regulation via estrogen receptor (ER) was addressed. METHODS AND RESULTS: Short-term treatment with I3C and DIM inhibited telomerase activity in leukaemia cells (>30 µM I3C; >3 µM DIM). In CD3/CD28 activated PBMC, inhibition was stronger, though (>3 µM I3C; >1 µM DIM). DIM long-term treatment resulted in DNA damage induction and proliferation inhibition in PBMC as determined by the comet assay and CFSE staining, respectively. A relevance of ERα/ß-AP1 signaling for telomerase inhibition on enzyme activity, but not transcription level became evident indicating a nonclassical mode for ER regulation of telomerase by DIM. CONCLUSION: Although desired in cancer cells, this study identified a potential adverse impact of I3C and DIM on telomerase action in normal human immune cells, partly mediated by an ER-dependent mechanism. These new findings should be considered for potential chronic high-dose chemoprevention strategies using these compounds.

Myocardial perfusion SPECT 2015 in Germany. Results of the 7th survey.

AIM: The working group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine presents the results of the 7th survey of myocardial perfusion SPECT (MPS) of the reporting year 2015. METHOD: 268 questionnaires (173 practices [PR], 67 hospitals [HO], 28 university hospitals [UH]) were evaluated. Results of the last survey from 2012 are set in squared brackets. RESULTS: MPS of 121 939 [105 941] patients were reported. 98 % [95 %] of all MPS were performed with Tc-99m radiopharmaceuticals and 2 % [5 %] with Tl-201. 78 % [79 %] of all patients were studied in PR, 14 % [15 %] in HO, and 8 % [6 %] in UH. A pharmacological stress test was performed in 43 % [39 %] (22 % [24 %] adenosine, 20 % [9 %] regadenoson, 1 % [6 %] dipyridamole or dobutamine). Attenuation correction was applied in 25 % [2009: 10 %] of MPS. Gated SPECT was performed in 78 % [70 %] of all rest MPS, in 80 % [73 %] of all stress and in 76 % [67 %] of all stress and rest MPS. 53 % [33 %] of all nuclear medicine departments performed MPS scoring by default, whereas 24 % [41 %] did not apply any quantification. 31 % [26 %] of all departments noticed an increase in their counted MPS and 29 % [29 %] no changes. Data from 89 departments which participated in all surveys showed an increase in MPS count of 11.1 % (PR: 12.2 %, HO: 4.8 %, UH: 18.4 %). 70 % [60 %] of the MPS were requested by ambulatory care cardiologists. CONCLUSION: The 2015 MPS survey reveals a high-grade adherence of routine MPS practice to current guidelines. The positive trend in MPS performance and number of MPS already observed in 2012 continues. Educational training remains necessary in the field of SPECT scoring.

TriFabs--Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery.

TriFabs are IgG-shaped bispecific antibodies (bsAbs) composed of two regular Fab arms fused via flexible linker peptides to one asymmetric third Fab-sized binding module. This third module replaces the IgG Fc region and is composed of the variable region of the heavy chain (VH) fused to CH3 with "knob"-mutations, and the variable region of the light chain (VL) fused to CH3 with matching "holes". The hinge region does not contain disulfides to facilitate antigen access to the third binding site. To compensate for the loss of hinge-disulfides between heavy chains, CH3 knob-hole heterodimers are linked by S354C-Y349C disulphides, and VH and VL of the stem region may be linked via VH44C-VL100C disulphides. TriFabs which bind one antigen bivalent in the same manner as IgGs and the second antigen monovalent "in between" these Fabs can be applied to simultaneously engage two antigens, or for targeted delivery of small and large (fluorescent or cytotoxic) payloads.

Prediction of VH-VL domain orientation for antibody variable domain modeling.

The antigen-binding site of antibodies forms at the interface of their two variable domains, VH and VL, making VH-VL domain orientation a factor that codetermines antibody specificity and affinity. Preserving VH-VL domain orientation in the process of antibody engineering is important in order to retain the original antibody properties, and predicting the correct VH-VL orientation has also been recognized as an important factor in antibody homology modeling. In this article, we present a fast sequence-based predictor that predicts VH-VL domain orientation with Q(2) values ranging from 0.54 to 0.73 on the evaluation set. We describe VH-VL orientation in terms of the six absolute ABangle parameters that have recently been proposed as a means to separate the different degrees of freedom of VH-VL domain orientation. In order to assess the impact of adjusting VH-VL orientation according to our predictions, we use the set of antibody structures of the recently published Antibody Modeling Assessment (AMA) II study. In comparison to the original AMAII homology models, we find an improvement in the accuracy of VH-VL orientation modeling, which also translates into an improvement in the average root-mean-square deviation with regard to the crystal structures.

Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties.

Several novel anti-CD20 monoclonal antibodies are currently in development with the aim of improving the treatment of B cell malignancies. Mutagenesis and epitope mapping studies have revealed differences between the CD20 epitopes recognized by these antibodies. Recently, X-ray crystallography studies confirmed that the Type I CD20 antibody rituximab and the Type II CD20 antibody obinutuzumab (GA101) differ fundamentally in their interaction with CD20 despite recognizing a partially overlapping epitope on CD20. The Type I CD20 antibodies rituximab and ofatumumab are known to bind to different epitopes. The differences suggest that the biological properties of these antibodies are not solely determined by their core epitope sequences, but also depend on other factors, such as the elbow hinge angle, the orientation of the bound antibody and differential effects mediated by the Fc region of the antibody. Taken together, these factors may explain differences in the preclinical properties and clinical efficacy of anti-CD20 antibodies.

Image quality and data quantification in dopamine transporter SPECT: advantage of 3-dimensional OSEM reconstruction?

PURPOSE: Reconstruction of striatal dopamine transporter (DAT) SPECT is commonly done by filtered back projection (FBP). We investigated if image reconstruction by 3-dimensional ordered-subset expectation maximization (3D-OSEM) with resolution recovery, which has recently become available for clinical routine, provides a relevant improvement. METHODS: I-FP-CIT SPECT studies of 18 patients with normal to severely decreased DAT binding were reconstructed by FBP, 2D-OSEM (without resolution recovery), and 3D-OSEM, each with 2 different filter settings, yielding 3 data set pairs of relatively low and high resolution and noise: FBP with seventh-order Butterworth filter [cutoff frequency, 0.36 Nyquist (FBPlow) and 0.45 Nyquist (FBPhigh)] and OSEM with 8 iterations and 8 subsets (2D-/3D-OSEMlow) and 6 iterations and 16 subsets (2D-/3D-OSEMhigh), each with 8-mm Gaussian filtering. Mean regional counts, variability of counts (coefficient of variation), and binding potential (BPND) were assessed by volume-of-interest analyses of the caudate nucleus, the putamen, and the occipital cortex (reference region). RESULTS: On visual inspection, both 2D- and 3D-OSEM-reconstructed images showed an optimal delineation of striatal structures, whereas variability (noise) of nonspecific cortical I-FP-CIT uptake was lowest (most homogenous) with FBPlow, slightly higher with 2D-/3D-OSEMlow, and notably higher for the other methods. Volume-of-interest analyses revealed no significant differences of counts in the occipital reference region in comparison to FBPlow (reference method). In caudate nucleus, counts and, consequently, BPND values increased significantly with FBPhigh (mean BPND change, +5.2%), 2D-OSEMlow/high (+3.7%/+6.2%), and, most notably, 3D-OSEMlow/high (+11.1%/+14.0%). In the putamen, this effect was less pronounced for FBPhigh (+1.8%) and 3D-OSEMlow/high (+5.6%/+6.8%) and failed to reach statistical significance for 2D-OSEMlow/high (-0.2%/+0.8%). Regression analyses indicated excellent correlations of BPND between FBPlow and all other methods (R > 0.97), with the highest regression slopes for 3D-OSEM (1.12-1.16) followed by FBPhigh (1.04-1.06) and then 2D-OSEM (1.01-1.04). The order of the variability of counts in the occipital cortex was as follows: FBPlow (12.5%), 2D-OSEMlow (13.9%), 3D-OSEMlow (14.2%), FBPhigh (15.1%), 2D-OSEMhigh (17.0%), and 3D-OSEMhigh (17.6%). CONCLUSIONS: Three-dimensional OSEM considerably improves DAT SPECT reconstruction by offering an optimal combination of high-resolution delineation of striatal structures, superior recovery of signal and BPND, and sufficiently homogeneous nonspecific tracer uptake of the reference region.

Chlormadinone acetate suppresses prostaglandin biosynthesis in human endometrial explants.

OBJECTIVE: To elucidate the mode of action of chlormadinone acetate (CMA) in reducing dysmenorrheic pain by studying the effects of CMA and dexamethasone (DEX) on messenger RNA (mRNA) abundance of cyclo-oxygenase-2 (COX-2), annexin-1 (ANXA1), glucocorticoid receptor (GR), progesterone receptor (PR), and concentrations of prostaglandin F(2α) (PGF(2α)) and leukotrienes B(4) (LTB(4)) and C(4) (LTC(4)) in human endometrial explants. DESIGN: Ex vivo study. SETTING: University hospital. PATIENT(S): Fifteen premenopausal patients undergoing surgery for benign gynecologic disorders. INTERVENTION(S): Endometrial explants were obtained by aspiration curettage and stimulated ex vivo with interleukin-1ß before exposure to CMA or DEX; mRNA levels were determined via reverse transcription-quantitative real-time polymerase chain reaction, and concentrations of arachidonic acid metabolites by enzyme immunoassays. MAIN OUTCOME MEASURE(S): Messenger RNA levels of COX-2, ANXA1, PR, and GR; concentrations of PGF(2α), LTB(4), and LTC(4) in endometrial explants treated with CMA or DEX. RESULT(S): In IL-1ß-treated explants COX-2 mRNA and PGF(2α), concentrations were significantly down-regulated by CMA but not by DEX. Chlormadinone acetate did not affect mRNA abundance of ANXA1, PR, and GR. CONCLUSION(S): Our data suggest that CMA is a suppressor of COX-2 expression. Comparison with DEX revealed that progestin-specific activity of CMA may mainly be responsible for suppression of prostaglandin biosynthesis in human endometrium.

Unprecedented long-term frequency stability with a microwave resonator oscillator.

This article reports on the long-term frequency stability characterization of a new type of cryogenic sapphire oscillator using an autonomous pulse-tube cryocooler as its cold source. This new design enables a relative frequency stability of better than 4.5 x 10(-15) over one day of integration. To the best of our knowledge, this represents the best long-term frequency stability ever obtained with a signal source based on a macroscopic resonator.

Opiate-induced dopamine release is modulated by severity of alcohol dependence: an [(18)F]fallypride positron emission tomography study.

BACKGROUND: Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of ß-endorphins stimulates µ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the ß-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. METHODS: Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). RESULTS: The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. CONCLUSIONS: The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found.