Publications by authors named "Verena Pichler"

67 Publications

Unexpected scaffold rearrangement product of pirenzepine found in commercial samples.

Sci Rep 2021 12 3;11(1):23397. Epub 2021 Dec 3.

Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria.

Pharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole. The rearrangement occurs under highly acidic conditions, which were believed to favour the dihydrochloride formation of pirenzepine. The rearranged products of pirenzepine and the structurally related telenzepine have significantly decreased affinity for the muscarinic acetylcholine receptor, the pharmacological target of these compounds. Fortunately, in situ rearrangement after oral application is no safety issue, as we show that reaction kinetics in gastric acid prevent rearrangement. The research community should consider appropriate measures to perform reliable receiving inspections in the commercial supply of well described and frequently used chemicals, in particular if experiments yield unexpected results.
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http://dx.doi.org/10.1038/s41598-021-02732-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642400PMC
December 2021

Immune Checkpoint Inhibitor Therapy Induces Inflammatory Activity in the Large Arteries of Lymphoma Patients under 50 Years of Age.

Biology (Basel) 2021 Nov 19;10(11). Epub 2021 Nov 19.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria.

Immune checkpoint inhibitors (ICI) have transformed the management of various cancers. Serious and potentially fatal cardiovascular toxicity, as well as a progression of atherosclerosis, have been described, mainly in elderly and comorbid patients. We investigated 117 arterial segments of 12 young (under 50 years of age), otherwise healthy lymphoma patients pre/post-ICI treatment using 2-[18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Maximum FDG standardized uptake values (SUV) and target-to-background ratios (TBRs) were calculated along arterial segments. Additionally, metabolic activities (SUV) of the bone marrow, spleen, and liver were analyzed. The levels of high-sensitivity C-reactive protein (hsCRP) were assessed. ICI therapy induced arterial inflammatory activity, detected by increased TBR in arterial segments without pre-existing inflammation (TBRneg_pre = 1.20 ± 0.22 vs. TBRneg_post = 1.71 ± 0.45, < 0.001), whereas already-inflamed lesions remained unchanged. Dormant calcified segments (Hounsfield Units-HU ≥ 130) showed a significant increase in TBR values after ICI treatment (TBRcalc_pre = 1.36 ± 0.38 vs. TBRcalc_post = 1.76 ± 0.42, < 0.001). FDG uptake measured in other organs and hsCRP levels remained unchanged after ICI therapy. Although the effects of ICI therapy on arterial inflammation are still incompletely understood, cancer immunotherapy might be a critical moderator of atherosclerosis with a subsequently increased risk of future cerebro- and/or cardiovascular events in young oncological patients.
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http://dx.doi.org/10.3390/biology10111206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615286PMC
November 2021

EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals: impact on safety and imaging quality.

EJNMMI Radiopharm Chem 2021 Oct 9;6(1):34. Epub 2021 Oct 9.

UMR 1253, iBrain, University of Tours, Tours, France.

This guideline on molar activity (A) and specific activity (A) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of A and A, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of A and A in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed. Furthermore, common A pitfalls and remedies are described. Finally, some aspects of A in relation the emergence of a new generation of highly sensitive PET scanners will be discussed.
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http://dx.doi.org/10.1186/s41181-021-00149-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502193PMC
October 2021

First-in-human brain PET imaging of the GluN2B-containing N-methyl-D-aspartate receptor with ()-C-Me-NB1.

J Nucl Med 2021 Oct 7. Epub 2021 Oct 7.

Animal Imaging Center-PET, Switzerland.

The N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer's disease and in the treatment of major depression by new fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of large interest as diagnostic and therapeutic targets. Recently, ()-C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits. Here, we report on the performance characteristics of this novel radioligand in a first-in-human PET study. Six healthy male subjects were scanned twice on a fully-integrated PET/MR scanner with ()-C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by standardized uptake values (SUV). Test-retest reliability was assessed with the absolute percentage difference (APD) and the coefficient of variation (COV). Exploratory total volumes of distribution (VT) were computed using an arterial input function and the Logan plot as well as a constrained two-tissue compartment model with K1/k2 coupled (2TCM). SUV was correlated with VT to investigate its potential as a surrogate marker of GluN2B expression. High and heterogeneous radioligand uptake was observed across the entire gray matter with reversible kinetics within the scan time. SUV APD ranged from 6.8 - 8.5% and COV from 4.9 - 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70-90 min and VT using Logan plot (Spearman's rho = 0.44). Correlation between VT Logan and 2TCM was r= 0.76. The novel radioligand, ()-C-Me-NB1, was highly effective in mapping GluN2B-enriched NMDARs in the human brain. With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDA receptor in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer's disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs.
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http://dx.doi.org/10.2967/jnumed.121.262427DOI Listing
October 2021

If It Works, Don't Touch It? A Cell-Based Approach to Studying 2-[F]FDG Metabolism.

Pharmaceuticals (Basel) 2021 Sep 9;14(9). Epub 2021 Sep 9.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria.

The glucose derivative 2-[F]fluoro-2-deoxy-D-glucose (2-[F]FDG) is still the most used radiotracer for positron emission tomography, as it visualizes glucose utilization and energy demand. In general, 2-[F]FDG is said to be trapped intracellularly as 2-[F]FDG-6-phosphate, which cannot be further metabolized. However, increasingly, this dogma is being questioned because of publications showing metabolism beyond 2-[F]FDG-6-phosphate and even postulating 2-[F]FDG imaging to depend on the enzyme hexose-6-phosphate dehydrogenase in the endoplasmic reticulum. Therefore, we aimed to study 2-[F]FDG metabolism in the human cancer cell lines HT1080, HT29 and Huh7 applying HPLC. We then compared 2-[F]FDG metabolism with intracellular tracer accumulation, efflux and the cells' metabolic state and used a graphical Gaussian model to visualize metabolic patterns. The extent of 2-[F]FDG metabolism varied considerably, dependent on the cell line, and was significantly enhanced by glucose withdrawal. However, the metabolic pattern was quite conserved. The most important radiometabolites beyond 2-[F]FDG-6-phosphate were 2-[F]FDMannose-6-phosphate, 2-[F]FDG-1,6-bisphosphate and 2-[F]FD-phosphogluconolactone. Enhanced radiometabolite formation under glucose reduction was accompanied by reduced efflux and mirrored the cells' metabolic switch as assessed via extracellular lactate levels. We conclude that there can be considerable metabolism beyond 2-[F]FDG-6-phosphate in cancer cell lines and a comprehensive understanding of 2-[F]FDG metabolism might help to improve cancer research and tumor diagnosis.
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http://dx.doi.org/10.3390/ph14090910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467898PMC
September 2021

Entomological Survey Confirms Changes in Mosquito Composition and Abundance in Senegal and Reveals Discrepancies among Results by Different Host-Seeking Female Traps.

Insects 2021 Jul 31;12(8). Epub 2021 Jul 31.

Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy.

Mosquitoes-borne diseases are major public health issues particularly in Africa. Vector control interventions and human-made environmental/climatic changes significantly affect the distribution and abundance of vector species. We carried out an entomological survey targeting host-seeking mosquitos in two different ecological contexts-coastal and inland-in Senegal, by CDC-light and BG-sentinel traps. Results show high predominance of (90%) and of within malaria vectors (46%), with mean numbers of females/trap/nights =8 and <1, respectively, reinforcing previous evidence of changes in species composition and abundance, highlighting thus increasing risk of transmission of filariasis and emerging arboviruses in the Senegambia region. From the methodological perspective, results show a higher specificity of BG traps for and of CDC traps for s.l. and highlight that, despite both traps target the host-seeking fraction of the population, they provide different patterns of species abundance, temporal dynamics and host-seeking activity, leading to possible misinterpretation of the species bionomics. This draws attention to the need of taking into account trapping performance, in order to provide realistic quantification of the number of mosquitoes per units of space and time, the crucial parameter for evaluating vector-human contact, and estimating risk of pathogen transmission.
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http://dx.doi.org/10.3390/insects12080692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396443PMC
July 2021

High-dose testosterone treatment reduces monoamine oxidase A levels in the human brain: A preliminary report.

Psychoneuroendocrinology 2021 11 6;133:105381. Epub 2021 Aug 6.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria. Electronic address:

The sex hormones testosterone and estradiol influence brain structure and function and are implicated in the pathogenesis, prevalence and disease course of major depression. Recent research employing gender-affirming hormone treatment (GHT) of gender dysphoric individuals and utilizing positron emission tomography (PET) indicates increased serotonin transporter binding upon high-dosages of testosterone treatment. Here, we investigated the effects of GHT on levels of monoamine oxidase A (MAO-A), another key target of antidepressant treatment. Participants underwent PET with the radioligand [C]harmine to assess cerebral MAO-A distribution volumes (V) before and four months after initiation of GHT. By the time this study was terminated for technical reasons, 18 transgender individuals undergoing GHT (11 transmen, TM and 7 transwomen, TW) and 17 cis-gender subjects had been assessed. Preliminary analysis of available data revealed statistically significant MAO-A V reductions in TM under testosterone treatment in six of twelve a priori defined regions of interest (middle frontal cortex (-10%), anterior cingulate cortex (-9%), medial cingulate cortex (-10.5%), insula (-8%), amygdala (-9%) and hippocampus (-8.5%, all p<0.05)). MAO-A V did not change in TW receiving estrogen treatment. Despite the limited sample size, pronounced MAO-A V reduction could be observed, pointing towards a potential effect of testosterone. Considering MAO-A's central role in regulation of serotonergic neurotransmission, changes to MAO-A V should be further investigated as a possible mechanism by which testosterone mediates risk for, symptomatology of, and treatment response in affective disorders.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105381DOI Listing
November 2021

Update on PET Tracer Development for Muscarinic Acetylcholine Receptors.

Pharmaceuticals (Basel) 2021 Jun 2;14(6). Epub 2021 Jun 2.

Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, 1090 Wien, Austria.

The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research.
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http://dx.doi.org/10.3390/ph14060530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229778PMC
June 2021

Reliability of task-specific neuronal activation assessed with functional PET, ASL and BOLD imaging.

J Cereb Blood Flow Metab 2021 11 2;41(11):2986-2999. Epub 2021 Jun 2.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.

Mapping the neuronal response during cognitive processing is of crucial importance to gain new insights into human brain function. BOLD imaging and ASL are established MRI methods in this endeavor. Recently, the novel approach of functional PET (fPET) was introduced, enabling absolute quantification of glucose metabolism at rest and during task execution in a single measurement. Here, we report test-retest reliability of fPET in direct comparison to BOLD imaging and ASL. Twenty healthy subjects underwent two PET/MRI measurements, providing estimates of glucose metabolism, cerebral blood flow (CBF) and blood oxygenation. A cognitive task was employed with different levels of difficulty requiring visual-motor coordination. Task-specific neuronal activation was robustly detected with all three imaging approaches. The highest reliability was obtained for glucose metabolism at rest. Although this dropped during task performance it was still comparable to that of CBF. In contrast, BOLD imaging yielded high performance only for qualitative spatial overlap of task effects but not for quantitative comparison. Hence, the combined assessment of fPET and ASL offers reliable and simultaneous absolute quantification of glucose metabolism and CBF at rest and task.
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http://dx.doi.org/10.1177/0271678X211020589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545051PMC
November 2021

Functional dynamics of dopamine synthesis during monetary reward and punishment processing.

J Cereb Blood Flow Metab 2021 11 30;41(11):2973-2985. Epub 2021 May 30.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.

The assessment of dopamine release with the PET competition model is thoroughly validated but entails disadvantages for the investigation of cognitive processes. We introduce a novel approach incorporating 6-[F]FDOPA uptake as index of the dynamic regulation of dopamine synthesis enzymes by neuronal firing. The feasibility of this approach is demonstrated by assessing widely described sex differences in dopamine neurotransmission. Reward processing was behaviorally investigated in 36 healthy participants, of whom 16 completed fPET and fMRI during the monetary incentive delay task. A single 50 min fPET acquisition with 6-[F]FDOPA served to quantify task-specific changes in dopamine synthesis. In men monetary gain induced stronger increases in ventral striatum dopamine synthesis than loss. Interestingly, the opposite effect was discovered in women. These changes were further associated with reward (men) and punishment sensitivity (women). As expected, fMRI showed robust task-specific neuronal activation but no sex difference. Our findings provide a neurobiological basis for known behavioral sex differences in reward and punishment processing, with important implications in psychiatric disorders showing sex-specific prevalence, altered reward processing and dopamine signaling. The high temporal resolution and magnitude of task-specific changes make fPET a promising tool to investigate functional neurotransmitter dynamics during cognitive processing and in brain disorders.
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http://dx.doi.org/10.1177/0271678X211019827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543667PMC
November 2021

Diagnostic Role of PET/CT Tracers in the Detection and Localization of Tumours Responsible for Ectopic Cushing's Syndrome.

Anticancer Res 2021 May;41(5):2477-2484

Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Background/aim: Positron emission tomography/computed tomography (PET/CT) plays an important role in cancer localization in ectopic Cushing's syndrome (ECS). However, the choice of the optimal tracer for investigation of this disease is still unclear. We aimed to evaluate the diagnostic feasibility of [F]fluoro-2-deoxyglucose ([F]FDG), [F]fluoro-L-dihydroxyphenylalanine ([F] FDOPA), and [Ga]-DOTA-1-Nal3-octreotide ([Ga]-DOTANOC) in ECS.

Patients And Methods: All PET/CT scans of patients admitted to our department for suspected ECS between 2010 and 2020 were retrospectively analysed.

Results: Collectively, 30 PET/CT examinations, 11 with [F]FDOPA, 11 with [F]FDG and 8 with [Ga]GaDOTANOC were conducted for 18 patients eligible for analysis. [F]FDG detected the tumour in 3/6 of the cases, [F]FDOPA in 3/4, and [Ga]GaDOTANOC in 3/3. [F]FDOPA was the only tracer without false positive results.

Conclusion: [Ga]GaDOTANOC and [F]FDOPA showed superior results compared to [F]FDG, although the sensitivity of the tracers might be influenced by the aetiology of the tumour underlying the ECS.
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http://dx.doi.org/10.21873/anticanres.15024DOI Listing
May 2021

A PCR-RFLP method for genotyping of inversion 2Rc in Anopheles coluzzii.

Parasit Vectors 2021 Mar 22;14(1):174. Epub 2021 Mar 22.

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, 46556, USA.

Background: Genotyping of polymorphic chromosomal inversions in malaria vectors such as An. coluzzii Coetzee & Wilkerson is important, both because they cause cryptic population structure that can mislead vector analysis and control and because they influence epidemiologically relevant eco-phenotypes. The conventional cytogenetic method of genotyping is an impediment because it is labor intensive, requires specialized training, and can be applied only to one gender and developmental stage. Here, we circumvent these limitations by developing a simple and rapid molecular method of genotyping inversion 2Rc in An. coluzzii that is both economical and field-friendly. This inversion is strongly implicated in temporal and spatial adaptations to climatic and ecological variation, particularly aridity.

Methods: Using a set of tag single-nucleotide polymorphisms (SNPs) strongly correlated with inversion orientation, we identified those that overlapped restriction enzyme recognition sites and developed four polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) assays that distinguish alternative allelic states at the tag SNPs. We assessed the performance of these assays using mosquito population samples from Burkina Faso that had been cytogenetically karyotyped as well as genotyped, using two complementary high-throughput molecular methods based on tag SNPs. Further validation was performed using mosquito population samples from additional West African (Benin, Mali, Senegal) and Central African (Cameroon) countries.

Results: Of four assays tested, two were concordant with the 2Rc cytogenetic karyotype > 90% of the time in all samples. We recommend that these two assays be employed in tandem for reliable genotyping. By accepting only those genotypic assignments where both assays agree, > 99% of assignments are expected to be accurate.

Conclusions: We have developed tandem PCR-RFLP assays for the accurate genotyping of inversion 2Rc in An. coluzzii. Because this approach is simple, inexpensive, and requires only basic molecular biology equipment, it is widely accessible. These provide a crucial tool for probing the molecular basis of eco-phenotypes relevant to malaria epidemiology and vector control.
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http://dx.doi.org/10.1186/s13071-021-04657-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983089PMC
March 2021

Novel genotyping approaches to easily detect genomic admixture between the major Afrotropical malaria vector species, Anopheles coluzzii and An. gambiae.

Mol Ecol Resour 2021 Jul 1;21(5):1504-1516. Epub 2021 Apr 1.

Dipartimento di Sanità Pubblica e Malattie Infettive, Istituto Pasteur Italia-Fondazione Cenci-Bolognetti, Università di Roma "Sapienza", Rome, Italy.

The two most efficient and most recently radiated Afrotropical vectors of human malaria - Anopheles coluzzii and An. gambiae - are identified by single-locus diagnostic PCR assays based on species-specific markers in a 4 Mb region on chromosome-X centromere. Inherently, these diagnostic assays cannot detect interspecific autosomal admixture shown to be extensive at the westernmost and easternmost extremes of the species range. The main aim of this study was to develop novel, easy-to-implement tools for genotyping An. coluzzii and An. gambiae-specific ancestral informative markers (AIMs) identified from the Anopheles gambiae 1000 genomes (Ag1000G) project. First, we took advantage of this large set of data in order to develop a multilocus approach to genotype 26 AIMs on all chromosome arms valid across the species range. Second, we tested the multilocus assay on samples from Guinea Bissau, The Gambia and Senegal, three countries spanning the westernmost hybridization zone, where conventional species diagnostic is problematic due to the putative presence of a novel "hybrid form". The multilocus assay was able to capture patterns of admixture reflecting those revealed by the whole set of AIMs and provided new original data on interspecific admixture in the region. Third, we developed an easy-to-use, cost-effective PCR approach for genotyping two AIMs on chromosome-3 among those included in the multilocus approach, opening the possibility for advanced identification of species and of admixed specimens during routine large scale entomological surveys, particularly, but not exclusively, at the extremes of the range, where WGS data highlighted unexpected autosomal admixture.
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http://dx.doi.org/10.1111/1755-0998.13359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252489PMC
July 2021

Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [C]Metoclopramide.

Mol Imaging Biol 2021 04 22;23(2):180-185. Epub 2021 Jan 22.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Purpose: To assess in healthy volunteers the whole-body distribution and dosimetry of [C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier.

Procedures: Ten healthy volunteers (five women, five men) were intravenously injected with 387 ± 49 MBq of [C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module.

Results: The majority of the administered dose of [C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [C]metoclopramide was 1.69 ± 0.26 μSv/MBq for female subjects and 1.55 ± 0.07 μSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81 ± 0.23 μGy/MBq and 8.78 ± 0.89 μGy/MBq) and the liver (6.80 ± 0.78 μGy/MBq and 4.91 ± 0.74 μGy/MBq) for female and male subjects, respectively.

Conclusions: [C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [C]metoclopramide was comparable to other C-labeled PET tracers.
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http://dx.doi.org/10.1007/s11307-021-01582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910245PMC
April 2021

A Novel Allele Specific Polymerase Chain Reaction (AS-PCR) Assay to Detect the V1016G Knockdown Resistance Mutation Confirms Its Widespread Presence in Populations from Italy.

Insects 2021 Jan 17;12(1). Epub 2021 Jan 17.

Dipartimento di Sanità Pubblica e Malattie Infettive, Università Sapienza, 00185 Rome, Italy.

Polymerase chain reaction (PCR)-based genotyping of mutations in the voltage-sensitive sodium channel () associated with resistance to pyrethroid insecticides is widely used and represents a potential early warning and monitoring system for insecticide resistance arising in mosquito populations, which are vectors of different human pathogens. In the secondary vector -an Asian species that has invaded and colonized the whole world, including temperate regions-sequencing of domain II of the gene is still needed to detect the V1016G mutation associated with pyrethroid resistance. In this study we developed and tested a novel allele-specific PCR (AS-PCR) assay to genotype the V1016G mutation in this species and applied it to the analysis of wild populations from Italy. The results confirm the high accuracy of the novel AS-PCR and highlight frequencies of the V1016G allele as >5% in most sampling sites, with peaks of 20-45% in coastal touristic sites where pyrethroid treatments are extensively implemented, mostly for mosquito nuisance reduction. The high frequency of this mutation observed in Italian populations should serve as a warning bell, advocating for increased monitoring and management of a phenomenon which risks neutralizing the only weapon today available to counteract (risks of) arbovirus outbreaks.
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http://dx.doi.org/10.3390/insects12010079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830166PMC
January 2021

CXCR4 PET imaging of mantle cell lymphoma using [Ga]Pentixafor: comparison with [F]FDG-PET.

Theranostics 2021 1;11(2):567-578. Epub 2021 Jan 1.

Dept. of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria.

For PET imaging of mantle cell lymphoma (MCL), [F]FDG (2-deoxy-2-[F]fluoro-D-glucose) is the currently recommended radiotracer, although uptake is variable and bone marrow evaluation is limited. In this prospective study, we evaluated the novel CXCR4 (G-protein-coupled C-X-C chemokine receptor type 4) tracer [Ga]Pentixafor in MCL patients, and compared it to [F]FDG. MCL patients underwent [Ga]Pentixafor-PET/MRI, and, if required for routine purposes, also [F]FDG-PET/MRI, before treatment. PET was evaluated separately for 23 anatomic regions (12 lymph node stations and 11 organs/tissues), using MRI as the main reference standard. Standardized uptake values (SUV and SUV) and tumor-to-background ratios (TBR and TBR) were calculated. General Estimation Equations (GEE) were used to compare [Ga]Pentixafor-PET and [F]FDG-PET sensitivities and positive predictive values (PPV). For bone marrow involvement, where biopsy served as the main reference standard, and splenic involvement, receiver operating characteristic curves were used to determine the optimal SUV and TBR cut-off values, and areas under the curve (AUC) were calculated. Twenty-two MCL patients were included. [Ga]Pentixafor-PET sensitivity (100%) was significantly higher than for [F]FDG-PET (75.2%) (<0.001), and PPV was slightly, but not significantly lower (94.0%.vs. 96.5%; =0.21). SUVs and TBRs were significantly higher for [Ga]Pentixafor-PET than for [F]FDG-PET (<0.001 in all cases); the greatest difference was observed for mean TBR, with 4.9 for [Ga]Pentixafor-PET and 2.0 for [F]FDG-PET. For bone marrow involvement, [Ga]Pentixafor-PET SUV showed an AUC of 0.92; and for splenic involvement, TBR showed an AUC of 0.81. [Ga]Pentixafor-PET may become an alternative to [F]FDG-PET in MCL patients, showing clearly higher detection rates and better tumor-to-background contrast.
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http://dx.doi.org/10.7150/thno.48620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738870PMC
August 2021

Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1.

Pharmaceuticals (Basel) 2020 Nov 30;13(12). Epub 2020 Nov 30.

Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria.

Muscarinic acetylcholine receptors (mAChRs) are a pivotal constituent of the central and peripheral nervous system. Yet, therapeutic and diagnostic applications thereof are hampered by the lack of subtype selective ligands. Within this work, we synthesized and chemically characterized three different stereoisomers of hydrobenzoin esters of arecaidine by NMR, HR-MS, chiral chromatography, and HPLC-logP. All compounds are structurally eligible for carbon-11 labeling and show appropriate stability in Dulbecco's phosphate-buffered saline (DPBS) and F12 cell culture medium. A competitive radioligand binding assay on Chinese hamster ovary cell membranes comprising the human mAChR subtypes M1-M5 showed the highest orthosteric binding affinity for subtype M1 and a strong influence of stereochemistry on binding affinity, which corresponds to in silico molecular docking experiments. K values toward M1 were determined as 99 ± 19 nM, 800 ± 200 nM, and 380 ± 90 nM for the (,)-, (,)-, and racemic (,)-stereoisomer, respectively, highlighting the importance of stereochemical variations in mAChR ligand development. All three stereoisomers were shown to act as antagonists toward mAChR M1 using a Fluo-4 calcium efflux assay. With respect to future positron emission tomography (PET) tracer development, the (,)-isomer appears especially promising as a lead structure due to its highest subtype selectivity and lowest K value.
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http://dx.doi.org/10.3390/ph13120437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760838PMC
November 2020

Prediction of response and survival after standardized treatment with 7400 MBq Lu-PSMA-617 every 4 weeks in patients with metastatic castration-resistant prostate cancer.

Eur J Nucl Med Mol Imaging 2021 05 30;48(5):1650-1657. Epub 2020 Oct 30.

Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Background And Aims: [Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT) is a new therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). However, identification of reliable prognostic factors is hampered by heterogeneous treatment regimens applied in previous studies. Hence, we sought clinical factors able to predict response and survival to PSMA-RLT in a homogenous group of patients, all receiving 7400 MBq every 4 weeks.

Patients And Methods: Data of 61 patients (mean age 71.6 ± 6.9 years, median basal PSA 70.7 [range 1.0-4890 μg/L]), pretreated with abiraterone/enzalutamide (75.4%) and docetaxel/cabazitaxel (68.9%), received three cycles of PSMA-RLT (mean 7321 ± 592 MBq) at four weekly intervals and were analyzed retrospectively. General medical conditions and laboratory parameters of every patients were regularly assessed. Response to therapy was based on PSA levels 1 month after the 3rd cycle. Binary logistic regression test and Kaplan-Meier estimates were used to evaluate predictors and overall survival (OS).

Results: Forty-nine (80.3%) patients demonstrated a therapy response in terms of any PSA decline, while 21 (19.7%) patients showed increase or no changes in their PSA levels. Baseline hemoglobin (Hb) significantly predicted PSA reductions of ≥ 50% 4 weeks after receiving the 3rd PSMA-RLT (P = 0.01, 95% CI: 1.09-2.09) with an AUC of 0.68 (95% CI: 0.54-0.81). The levels of basal Hb and basal PSA were able to predict survival of patients, both P < 0.05 (relative risk 1.51 and 0.79, 95% CI: 1.09-2.09 and 0.43-1.46), respectively. In comparison to patients with reduced basal Hb, patients with normal basal Hb levels lived significantly longer (median survival not reached vs. 89 weeks, P = 0.016). Also, patients with basal PSA levels ≤ 650 μg/L had a significantly longer survival than patients with basal PSA levels > 650 μg/L (median survival not reached vs. 97 weeks, P = 0.031). Neither pretreatments with abiraterone/enzalutamide or docetaxel/cabazitaxel nor distribution of metastasis affected survival and rate of response to PSMA-RLT.

Conclusion: Basal Hb level is an independent predictor for therapy response and survival in patients receiving PSMA-RLT every 4 weeks. Both baseline PSA ≤ 650 μg/L and normal Hb levels were associated with longer survival.
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http://dx.doi.org/10.1007/s00259-020-05082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113146PMC
May 2021

Assessment of left and right ventricular functional parameters using dynamic dual-tracer [N]NH3 and [F]FDG PET/MRI.

J Nucl Cardiol 2020 Oct 22. Epub 2020 Oct 22.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Floor 5L, 1090, Vienna, Austria.

Background: Cardiac positron emission tomography/magnetic resonance imaging (PET/MRI) can assess various cardiovascular diseases. In this study, we intra-individually compared right (RV) and left ventricular (LV) parameters obtained from dual-tracer PET/MRI scan.

Methods: In 22 patients with coronary heart disease (69 ± 9 years) dynamic [N]NH (NH) and [F]FDG (FDG) PET scans were acquired. The first 2 minutes were used to calculate LV and RV first-pass ejection fraction (FPEF). Additionally, LV end-systolic (LVESV) and end-diastolic (LVEDV) volume and ejection fraction (LVEF) were calculated from the early (EP) and late-myocardial phases (LP). MRI served as a reference.

Results: RVFPEF and LVFPEF from FDG and NH as well as RVEF and LVEF from MRI were (28 ± 11%, 32 ± 15%), (32 ± 11%, 41 ± 14%) and (42 ± 16%, 45 ± 19%), respectively. LVESV, LVEDV and LVEF from EP FDG and NH in 8 and 16 gates were [71 (15 to 213 mL), 98 (16 to 241 mL), 32 ± 17%] and [50 (17 to 206 mL), 93 (13 to 219 mL), 36 ± 17%] as well as [60 (19 to 360 mL), 109 (56 to 384 mL), 41 ± 22%] and [54 (16 to 371 mL), 116 (57 to 431 mL), 46 ± 24%], respectively. Moreover, LVESV, LVEDV and LVEF acquired from LP FDG and NH were (85 ± 63 mL, 138 ± 63 mL, 47 ± 19%) and (79 ± 56 mL, 137 ± 63 mL, 47 ± 20%), respectively. The LVESV, LVEDV from MRI were 93 ± 66 mL and 153 ± 71 mL, respectively. Significant correlations were observed for RVFPEF and LVFPEF between FDG and MRI (R = .51, P = .01; R = .64, P = .001), respectively. LVESV, LVEDV, and LVEF revealed moderate to strong correlations to MRI when they acquired from EP FDG and NH in 16 gates (all R > .7, P = .000). Similarly, all LV parameters from LP FDG and NH correlated good to strongly positive with MRI (all R > .7, and P < .001), except EDV from NH3 weakly correlated to EDV of MRI (R = .54, P < .05). Generally, Bland-Altman plots showed good agreements between PET and MRI.

Conclusions: Deriving LV and RV functional values from various phases of dynamic NH and FDG PET is feasible. These results could open a new perspective for further clinical applications of the PET examinations.
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http://dx.doi.org/10.1007/s12350-020-02391-yDOI Listing
October 2020

Impaired Clearance From the Brain Increases the Brain Exposure to Metoclopramide in Elderly Subjects.

Clin Pharmacol Ther 2021 03 14;109(3):754-761. Epub 2020 Oct 14.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

The antiemetic and gastroprokinetic drug metoclopramide is a weak substrate of the blood-brain barrier (BBB) efflux transporter P-gp and displays central nervous system (CNS) side effects (i.e., extrapyramidal symptoms and tardive dyskinesia) caused by dopamine D receptor blockade in the basal ganglia. These side effects occur with a higher incidence in elderly people. We used positron emission tomography to assess the brain distribution of [ C]metoclopramide in young (n = 11, 26 ± 3 years) and elderly (n = 7, 68 ± 9 years) healthy men both after administration of a microdose (9 ± 7 µg) and a microdose co-injected with a therapeutic dose of unlabeled metoclopramide (10 mg). For both doses, elderly subjects had a significantly higher total volume of distribution (V ) of [ C]metoclopramide in the basal ganglia than young subjects (microdose: +26%, therapeutic dose: +41%). Increases in V (= K /k ) were caused by significant decreases in the transfer rate constant of [ C]metoclopramide from brain into plasma (k , microdose: -18%, therapeutic dose: -30%), whereas the distributional clearance from plasma into brain (K ) remained unaltered. This reduction in the clearance of [ C]metoclopramide (k ) from the brains of elderly subjects may be caused by an age-related decrease in the activity of P-gp at the BBB and may contribute to the higher incidence of CNS side effects of metoclopramide in the aged population. Our data suggest that an age-associated decrease in the clearance properties of the BBB may modulate the CNS effects or side effects of clinically used P-gp substrates.
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http://dx.doi.org/10.1002/cpt.2052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983943PMC
March 2021

Immune Checkpoint Inhibitor Therapy Induces Inflammatory Activity in Large Arteries.

Circulation 2020 12 8;142(24):2396-2398. Epub 2020 Sep 8.

Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy (R.C., V.P., M.M., G.K., A.H., X.L., M.H.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048708DOI Listing
December 2020

Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers.

Eur J Med Chem 2020 Oct 19;204:112623. Epub 2020 Jul 19.

Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Austria. Electronic address:

Supported by their involvement in many neurodegenerative disorders, muscarinic acetylcholine receptors (mAChRs) are an interesting target for PET imaging. Nevertheless, no radiotracer is established in clinical routine. Within this work we aim to develop novel PET tracers based on the structure of arecoline. Fifteen novel arecoline derivatives were synthesized, characterized and tested for their affinity to the mAChRs M1-M5 and the conceivable off-target acetylcholinesterase. Five arecoline derivatives and arecoline were labeled with carbon-11 in good yields. Arecaidine diphenylmethyl ester (3b), arecaidine bis(4-fluorophenyl)methyl ester (3c) and arecaidine (4-bromophenyl)(4-fluorophenyl)methyl ester (3e) showed a tremendous gain in mAChR affinity compared to arecoline and a pronounced subtype selectivity for M1. Metabolic stability and serum protein binding of [C]3b and [C]3c were in line with properties of established brain tracers. Nonspecific binding of [C]3c was prevalent in kinetic and endpoint experiment on living cells as well as in autoradiography on native mouse brain sections, which motivates us to decrease the lipophilicity of this substance class prior to in vivo experiments.
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http://dx.doi.org/10.1016/j.ejmech.2020.112623DOI Listing
October 2020

In Human Visualization of Ibrutinib-Induced CLL Compartment Shift.

Cancer Immunol Res 2020 08 24;8(8):984-989. Epub 2020 Jun 24.

Division of Hematology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Bruton tyrosine kinase inhibitor ibrutinib is effective in treating chronic lymphocytic leukemia (CLL). However, after ibrutinib treatment initiation, patients frequently experience an increase of CLL blood cell count. This phenomenon in clinical practice is thought to reflect a "compartment shift" of CLL cells from lymph nodes to the peripheral blood, but the actual shifting has not yet been demonstrated. Using [Ga]Pentixafor-PET/MRI for CXCR4 visualization, we here provide images of topical changes of CLL cells upon ibrutinib treatment. Within the first month of ibrutinib treatment, mean standardized [Ga]Pentixafor uptake decreased in the bone marrow and lymph nodes, whereas [Ga]Pentixafor uptake increased in the spleen. Leukocytosis rose, as did numbers of CXCR4 (tissue-resident) CLL cells. Volumes of lymph nodes and spleen decreased. Upon longer ibrutinib treatment, leukocytosis decreased, followed by a decrease of [Ga]Pentixafor uptake in the spleen. These results support the preexisting clinical hypothesis of a "compartment shift" of CLL cells from the lymph nodes to the peripheral blood, but also refine the mechanistic model by describing early clearing of the bone marrow and redistribution of CLL cells to the orthotopic splenic cavernous system in response to ibrutinib treatment.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373313PMC
August 2020

Behavioural plasticity of Anopheles coluzzii and Anopheles arabiensis undermines LLIN community protective effect in a Sudanese-savannah village in Burkina Faso.

Parasit Vectors 2020 Jun 1;13(1):277. Epub 2020 Jun 1.

Dipartimento di Sanità Pubblica e Malattie Infettive, Laboratory affiliated to Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Sapienza Università di Roma, Rome, 00185, Italy.

Background: Despite the overall major impact of long-lasting insecticide treated nets (LLINs) in eliciting individual and collective protection to malaria infections, some sub-Saharan countries, including Burkina Faso, still carry a disproportionately high share of the global malaria burden. This study aims to analyse the possible entomological bases of LLIN limited impact, focusing on a LLIN-protected village in the Plateau Central region of Burkina Faso.

Methods: Human landing catches (HLCs) were carried out in 2015 for 12 nights both indoors and outdoors at different time windows during the highest biting activity phase for Anopheles gambiae (s.l.). Collected specimens were morphologically and molecularly identified and processed for Plasmodium detection and L1014F insecticide-resistance allele genotyping.

Results: Almost 2000 unfed An. gambiae (s.l.) (54% Anopheles coluzzii and 44% Anopheles arabiensis) females landing on human volunteers were collected, corresponding to a median number of 23.5 females/person/hour. No significant differences were observed in median numbers of mosquitoes collected indoors and outdoors, nor between sporozoite rates in An. coluzzii (6.1%) and An. arabiensis (5.5%). The estimated median hourly entomological inoculation rate (EIR) on volunteers was 1.4 infective bites/person/hour. Results do not show evidence of the biting peak during night hours typical for An. gambiae (s.l.) in the absence of bednet protection. The frequency of the L1014F resistant allele (n = 285) was 66% in An. coluzzii and 38% in An. arabiensis.

Conclusions: The observed biting rate and sporozoite rates are in line with the literature data available for An. gambiae (s.l.) in the same geographical area before LLIN implementation and highlight high levels of malaria transmission in the study village. Homogeneous biting rate throughout the night and lack of preference for indoor-biting activity, suggest the capacity of both An. coluzzii and An. arabiensis to adjust their host-seeking behaviour to bite humans despite bednet protection, accounting for the maintenance of high rates of mosquito infectivity and malaria transmission. These results, despite being limited to a local situation in Burkina Faso, represent a paradigmatic example of how high densities and behavioural plasticity in the vector populations may contribute to explaining the limited impact of LLINs on malaria transmission in holo-endemic Sudanese savannah areas in West Africa.
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http://dx.doi.org/10.1186/s13071-020-04142-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268364PMC
June 2020

Reconfiguration of functional brain networks and metabolic cost converge during task performance.

Elife 2020 04 21;9. Epub 2020 Apr 21.

QIMR Berghofer Medical Research Institute, Brisbane, Australia.

The ability to solve cognitive tasks depends upon adaptive changes in the organization of whole-brain functional networks. However, the link between task-induced network reconfigurations and their underlying energy demands is poorly understood. We address this by multimodal network analyses integrating functional and molecular neuroimaging acquired concurrently during a complex cognitive task. Task engagement elicited a marked increase in the association between glucose consumption and functional brain network reorganization. This convergence between metabolic and neural processes was specific to feedforward connections linking the visual and dorsal attention networks, in accordance with task requirements of visuo-spatial reasoning. Further increases in cognitive load above initial task engagement did not affect the relationship between metabolism and network reorganization but only modulated existing interactions. Our findings show how the upregulation of key computational mechanisms to support cognitive performance unveils the complex, interdependent changes in neural metabolism and neuro-vascular responses.
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http://dx.doi.org/10.7554/eLife.52443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176400PMC
April 2020

Response evaluation of SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus using F-FDG PET/MRI.

BMJ Open Diabetes Res Care 2020 03;8(1)

Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.

Introduction: Inhibitors of sodium-glucose linked transporter-2 (SGLT2i) are enhancing glucose excretion in the proximal renal tubules, and thus are increasingly used to lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM). The glucose analog 2-deoxy-2-(F) fluoro-D-glucose (FDG) can be used to quantify renal function in vivo, and due to an affinity for SGLT2 could also provide information about SGLT2 transporter function. Our objectives in this study were, therefore, to assess the impact of SGLT2i on renal function parameters in patients with T2DM and identify predictive parameters of long-term response to SGLT2i using dynamic FDG positron emission tomography (PET)/MRI.

Methods: PET FDG renal function measures such as mean transit time (MTT) and general renal performance (GRP) together with glomerular filtration rate (GFR) were determined in 20 patients with T2DM before (T2DM) and 2 weeks after initiation of therapy with SGLT2i (T2DM). Additionally, dynamic FDG PET data of 24 healthy subjects were used as controls.

Results: MTT in T2DM was significantly higher than in healthy controls (5.7 min vs 4.3 min, p=0.012) and significantly decreased to 4.4 min in T2DM (p=0.004). GRP of T2DM was higher than of T2DM (5.2 vs 4.7, p=0.02) and higher but not significantly than of healthy individuals (5.2 vs 5.1, p=0.34). Expectedly, GFR of healthy participants was significantly higher than of T2DM and T2DM (122 vs 92 and 86 mL/min/1.73 m², respectively; p<0.001). The higher the GRP value in kidneys of T2DM, the lower was the glycated hemoglobin level 3 months after therapy initiation.

Conclusion: MTT and GRP values of patients with T2DM shifted significantly toward values of healthy control 2 weeks after therapy with SGLT2i begins. GRP in T2DM was associated with better long-term glycemic response 3 months after initiation of therapy.

Trial Registration Number: NCT03557138.
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http://dx.doi.org/10.1136/bmjdrc-2019-001135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206902PMC
March 2020

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D receptor agonist radioligand study.

Transl Psychiatry 2020 01 8;10(1). Epub 2020 Jan 8.

Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D receptor agonist radioligand [C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.
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http://dx.doi.org/10.1038/s41398-019-0681-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026156PMC
January 2020

Topologically Guided Prioritization of Candidate Gene Transcripts Coexpressed with the 5-HT1A Receptor by Combining In Vivo PET and Allen Human Brain Atlas Data.

Cereb Cortex 2020 05;30(6):3771-3780

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

The serotonin-1A receptor (5-HT1AR) represents a viable target in the treatment of disorders of the brain. However, development of psychiatric drugs continues to be hindered by the relative inaccessibility of brain tissue. Although the efficacy of drugs selective for the 5-HT1AR has not been proven, research continues to focus on drugs that influence this receptor subtype. To further knowledge on this topic, we investigated the topological coexpression patterns of the 5-HT1AR. We calculated Spearman's rho for the correlation of positron emission tomography-binding potentials (BPND) of the 5-HT1AR assessed in 30 healthy subjects using the tracer [carbonyl-11C]WAY-100635 and predicted whole-brain mRNA expression of 18 686 genes. After applying a threshold of r > 0.3 in a leave-one-out cross-validation of the prediction of mRNA expression, genes with ρ ≥ 0.7 were considered to be relevant. In cortical regions, 199 genes showed high correlation with the BPND of the 5-HT1AR, in subcortical regions 194 genes. Using our approach, we could consolidate the role of BDNF and implicate new genes (AnxA8, NeuroD2) in serotonergic functioning. Despite its explorative nature, the analysis can be seen as a gene prioritization approach to reduce the number of genes potentially connected to 5-HT1AR functioning and guide future in vitro studies.
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http://dx.doi.org/10.1093/cercor/bhz341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232988PMC
May 2020

Highly specific PCR-RFLP assays for karyotyping the widespread 2Rb inversion in malaria vectors of the Anopheles gambiae complex.

Parasit Vectors 2020 Jan 10;13(1):16. Epub 2020 Jan 10.

Eck Institute for Global Health, & Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, 46556, USA.

Background: Chromosomal inversion polymorphisms play a role in adaptation to heterogeneous environments. Inversion polymorphisms are implicated in the very high ecological flexibility of the three main malaria vector species of the Afrotropical Anopheles gambiae complex, facilitating the exploitation of anthropogenic environmental modifications and promoting a strong association with humans. In addition to extending the species' spatial and temporal distribution, inversions are associated with epidemiologically relevant mosquito behavior and physiology, underscoring their medical importance. We here present novel PCR-RFLP based assays strongly predictive of genotype for the cosmopolitan 2Rb inversion in An. coluzzii and An. gambiae, a development which overcomes the numerous constraints inherent to traditional cytological karyotyping.

Methods: We designed PCR-RFLP genotyping assays based on tag SNPs previously computationally identified as strongly predictive (> 95%) of 2Rb genotype. We targeted those tags whose alternative allelic states destroyed or created the recognition site of a commercially available restriction enzyme, and designed assays with distinctive cleavage profiles for each inversion genotype. The assays were validated on 251 An. coluzzii and 451 An. gambiae cytologically karyotyped specimens from nine countries across Africa and one An. coluzzii laboratory colony.

Results: For three tag SNPs, PCR-RFLP assays (denoted DraIII, MspAI, and TatI) reliably produced robust amplicons and clearly distinguishable electrophoretic profiles for all three inversion genotypes. Results obtained with the DraIII assay are ≥ 95% concordant with cytogenetic assignments in both species, while MspAI and TatI assays produce patterns highly concordant with cytogenetic assignments only in An. coluzzii or An. gambiae, respectively. Joint application of species-appropriate pairs of assays increased the concordance levels to > 99% in An. coluzzii and 98% in An. gambiae. Potential sources of discordance (e.g. imperfect association between tag and inversion, allelic dropout, additional polymorphisms in the restriction target site, incomplete or failed restriction digestion) are discussed.

Conclusions: The availability of highly specific, cost effective and accessible molecular assays for genotyping 2Rb in An. gambiae and An. coluzzii allows karyotyping of both sexes and all developmental stages. These novel tools will accelerate deeper investigations into the role of this ecologically and epidemiologically important chromosomal inversion in vector biology.
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http://dx.doi.org/10.1186/s13071-019-3877-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954590PMC
January 2020
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