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Introduction Liver transplantation (LT) is a crucial treatment for end-stage alcoholic liver disease, the most common liver disease in developed countries. Personality traits and cognition, a relatively stable characteristics, are known to be significantly associated with quality of life (QoL). However, how they impact QoL in long-term LT survivors is unclear. Objectives The study aimed to assess the associations between personality traits and cognition and their impact on the QoL in long-term LT survivors. Methods First time LT recipients due to end-stage alcohol liver disease without long-term complications were consecutively included during standard outpatient care. Sociodemographic and clinical data was collected. Personality traits were assessed using 50-item International Personality Item Pool of the Five-factor model (IPIP), cognition using Mini Mental State Examination (MMSE), and QoL using EuroQoL-5D (EQ-5D) questionnaire. Results Eighty-three participants were included (mean age 62.9±7.03y, 90.6% male). Median MMSE score was 27±2.00, and median years since LT 5±2.91. Significant positive associations were found between IPIP dimensions Extraversion (B=0.297, p

Salt marshes and seagrass meadows can sequester and store high quantities of organic carbon (OC) in their sediments relative to other marine and terrestrial habitats. Assessing carbon stocks, carbon sources, and the transfer of carbon between habitats within coastal seascapes are each integral in identifying the role of blue carbon habitats in coastal carbon cycling. Here, we quantified carbon stocks, sources, and exchanges in seagrass meadows, salt marshes, and unvegetated sediments in six bays along the California coast. In the top 20 cm of sediment, the salt marshes contained approximately twice as much OC as seagrass meadows did, 4.92 ± 0.36 kg OC m−2 compared to 2.20 ± 0.24 kg OC m−2, respectively. Both salt marsh and seagrass sediment carbon stocks were higher than previous estimates from this region but lower than global and US-wide averages, respectively. Seagrass-derived carbon was deposited annually into adjacent marshes during fall seagrass senescence. However, isotope mixing models estimate that negligible amounts of this seagrass material were ultimately buried in underlying sediment. Rather, the vast majority of OC in sediment across sites was likely derived from planktonic/benthic diatoms and/or C3 salt marsh plants.

Public transportation buses are places of intense movement of people, which may constitute important dispersal vehicles of microorganisms and parasites. In such context, this paper sought to assess the microbial and parasitological diversity inside urban and periurban buses that run four routes in Divinópolis MG. For the microbial study, 80 sample collections were made by using a sterile swab containing Stuart transport medium and were taken to the Microbiology Laboratory of the UEMG – Divinópolis MG, in order to perform the laboratorial tests. For search about eggs and cysts of intestinal parasites, 80 samples were collected, out of which 40 were collected by using the Graham method, and 40 were collected by using swab. Two smears of each sample were analyzed. In the microbial research, 1097 CFU mL-1 of heterotrophic bacteria were analyzed. Through mass spectrometry eleven potentially pathogenic species of bacteria were identified out of which seven were identified as antibiotics-resistant. In the parasitological analysis through the Graham method a probable cyst of Blastocystis hominis and an egg similar to those of Hymenolepis sp. were identified. Through the use of swab four eggs similar to those of Ascaris sp. and a probable cyst of B.hominis were also identified. The bacterial and parasitological prevalence was higher on buses that run in hospital and periurban areas. Based on results obtained it was possible to outline a profile until then unknown of the bacteria and parasites present in some of the main public transportation routes of Divinópolis MG.

This paper deals with the changes in soil active acidity, mobile aluminium, base saturation, iron and manganese under the influence of quicklime (QL), mixture of soft lithothamnian limestone (SLL) and dolomite (D), and special natural amendments (SNA) based on zeolite tuff. Investigations were carried out on pseudogley of mesoelevations, dystric. The four-year trial was set up according to the Latin rectangle method with 18 trial treatments in four replications. While SNA based on zeolite tuff had little effect on changes of the studied parameters, traditional lime materials (LM), owing also to the fact that they were applied at several times higher rates, had a very positive effect. Soil acidity, iron and manganese were reduced under their influence, mobile aluminium, particularly under their higher rate, was fully blocked or reduced within tolerable limits, and base saturation was raised to a satisfactory level. Effects of SNA depended on the ratio of zeolite tuff and the lime component in them. It could be presupposed that their main efficiency happened in the domain of ion exchange with a positive impact on soil fertility.

The conception of these investigations is based on the premise that a way should be found to eliminate, or at least mitigate, the harmful effect of excessive soil acidity without resorting to the massive and costly measures of liming. The main issue addressed in this study is how to increase crop yield by increasing nutrient availability rather than how to neutralize the soil. This as well as our earlier investigations, conducted on pseudogley of mesoelevations, indicate that this can be achieved by the application of special natural amendments (SNA) based on zeolite tuff, under the name Agrarvital (AV), in which clinoptilolite prevails while the remaining part is a mixture of soft lithothamnian limestone and dolomite (SLL+D). These amendments enhance ion exchange in the soil and their activation at a considerably lower pH than it is the case after liming. Fertilizing value of Agrarvital (AV) and lime materials (LM) was evaluated according to the yields achieved and some yield components of the crops grown. The results point to the good fertilizing effect of AV upon yields of winter wheat, maize, soybean and winter barley, equal to or better than the effect of conventional LM applied at several times higher rates.

Cholangiocarcinoma (CCA) is a type of primary liver cancer originating from the biliary tract epithelium, characterized by limited treatment options for advanced cases and low survival rates. This study aimed to establish an orthotopic mouse model for CCA and monitor tumor growth using PET/MR imaging. Murine CCA cells were implanted into the liver lobe of male C57BL/6J mice. The imaging groups included contrast-enhanced (CE) MR, CE-MR with static [ 18 F]FDG-PET, and dynamic [ 18 F]FDG-PET. Tumor volume and FDG uptake were measured weekly over four weeks. Early tumor formation was visible in CE-MR images, with a gradual increase in volume over time. Dynamic FDG-PET revealed an increase in the metabolic glucose rate (MRGlu) over time. Blood analysis showed pathological changes in liver-related parameters. Lung metastases were observed in nearly all animals after four weeks. The study concludes that PET-MR imaging effectively monitors tumor progression in the CCA mouse model, providing insights into CCA development and potential treatment strategies.

Cardiac conduction involves electrical activity from one myocyte to another, creating coordinated contractions in each. Disruptions in the conducting system, such as left bundle branch block (LBBB), can result in premature activation of specific regions of the heart, leading to heart failure and increased morbidity and mortality. Structural alterations in T-tubules and the sarcoplasmic reticulum can lead to dyssynchrony, a condition that can be treated by cardiac resynchronization therapy (CRT), which stands as a cornerstone in this pathology. The heterogeneity in patient responses underscored the necessity of improving the diagnostic approach. Vectocardiography, ultra-high-frequency ECG, 3D echocardiography, and electrocardiographic imaging seem to offer advanced precision in identifying optimal candidates for CRT in addition to the classic diagnostic methods. The advent of His bundle pacing and left bundle branch pacing further refined the approach in the treatment of dyssynchrony, offering more physiological pacing modalities that promise enhanced outcomes by maintaining or restoring the natural sequence of ventricular activation. HOT-CRT emerges as a pivotal innovation combining the benefits of CRT with the precision of His bundle or left bundle branch area pacing to optimize cardiac function in a subset of patients where traditional CRT might fall short.

Nanodiamonds (NDs) are emerging as a novel nanoparticle class with growing interest in medical applications. The surface coating of NDs can be modified by attaching binding ligands or imaging probes, turning them into multi-modal targeting agents. In this investigation, we assessed the targeting efficacy of octreotide-functionalized 68 Ga-radiolabelled NDs for cancer imaging and compared it with the tumor uptake using [ 68 Ga]Ga-DOTA-TOC. In vivo studies in mice bearing AR42J tumors demonstrated the highest accumulation of the radiolabeled functionalized NDs in the liver and spleen, with relatively low tumor uptake compared to [ 68 Ga]Ga-DOTA-TOC. Our findings suggest that, within the scope of this study, functionalization did not enhance the tumor-targeting capabilities of NDs.

Background: During infection, neutrophil extracellular traps (NETs) are associated with severity of pulmonary diseases such as acute respiratory disease syndrome. NETs induce subsequent immune responses, are directly cytotoxic to pulmonary cells, and are highly procoagulant. Anticoagulation treatment was shown to reduce in-hospital mortality, indicating thromboinflammatory complications. However, data are sparsely available on the involvement of NETs in secondary events after virus clearance, which can lead to persistent lung damage and postacute sequelae with chronic fatigue and dyspnea., Objectives: This study focuses on late-phase events using a murine model of viral lung infection with postacute sequelae after virus resolution., Methods: C57BL/6JRj mice were infected intranasally with the betacoronavirus murine coronavirus (MCoV, strain MHV-A95), and tissue samples were collected after 2, 4, and 10 days. For NET modulation, mice were pretreated with OM-85 or GSK484 and DNase I were administered intraperitoneally between days 2 to 5 and days 4 to 7, respectively., Results: Rapid, platelet-attributed thrombus formation was followed by a second, late phase of thromboinflammation. This phase was characterized by negligible virus titers but pronounced tissue damage, apoptosis, oxidative DNA damage, and presence of NETs. Inhibition of NETs during the acute phase did not impact virus burden but decreased lung cell apoptosis by 67% and oxidative stress by 94%. Prevention of neutrophil activation by immune training before virus infection reduced damage by 75%, NETs by 31%, and pulmonary thrombi by 93%., Conclusion: NETs are detrimental inducers of tissue damage during respiratory virus infection but do not contribute to virus clearance., Competing Interests: Declaration of competing interests M.S., P.G., P.H., M.B., R.P., T.F., R.N., B.H., J.W., C.H., B.K.P., J.B.K-P. declare no conflict of interest. P.J.H. is a consultant for OM Pharma., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [ 11 C]metoclopramide to measure decreased cerebral P-gp function, we performed [ 11 C]metoclopramide PET scans without (baseline) and with partial P-gp inhibition by tariquidar in wild-type, heterozygous Abcb1a/b (+/-) and homozygous Abcb1a/b (-/-) mice as models with controlled levels of cerebral P-gp expression. Brains were collected to quantify P-gp expression with immunohistochemistry. Brain uptake of [ 11 C]metoclopramide was expressed as the area under the brain time-activity curve (AUC brain ) and compared with data previously obtained with ( R )-[ 11 C]verapamil and [ 11 C] N -desmethyl-loperamide. Abcb1a/b (+/-) mice had intermediate P-gp expression compared to wild-type and Abcb1a/b (-/-) mice. In baseline scans, all three radiotracers were able to discriminate Abcb1a/b (-/-) from wild-type mice (2.5- to 4.6-fold increased AUC brain , p ≤ 0.0001). However, only [ 11 C]metoclopramide could discriminate Abcb1a/b (+/-) from wild-type mice (1.46-fold increased AUC brain , p ≤ 0.001). After partial P-gp inhibition, differences in [ 11 C]metoclopramide AUC brain between Abcb1a/b (+/-) and wild-type mice (1.39-fold, p ≤ 0.001) remained comparable to baseline. There was a negative correlation between baseline [ 11 C]metoclopramide AUC brain and ex-vivo -measured P-gp immunofluorescence (r =  - 0.9875, p ≤ 0.0001). Our data suggest that [ 11 C]metoclopramide is a sensitive radiotracer to measure moderate, but (patho-)physiologically relevant decreases in cerebral P-gp function without the need to co-administer a P-gp inhibitor., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a highly abundant efflux transporter in the lungs, which protects cells from toxins and oxidative stress and has been implicated in the pathophysiology of chronic obstructive pulmonary disease and cystic fibrosis. There is evidence from in vitro studies that the inhaled glucocorticoid budesonide can inhibit MRP1 activity. We used positron emission tomography (PET) imaging with 6-bromo-7-[ 11 C]methylpurine ([ 11 C]BMP), which is transformed in vivo into a radiolabeled MRP1 substrate, to assess whether intratracheally (i.t.) aerosolized budesonide affects pulmonary MRP1 activity in rats. Three groups of rats (n = 5-6 each) underwent dynamic PET scans of the lungs after i.t. aerosolization of either [ 11 C]BMP alone, or [ 11 C]BMP mixed with either budesonide (0.04 mg, corresponding to the maximum soluble dose) or the model MRP1 inhibitor MK571 (2 mg). From PET-measured radioactivity concentration-time curves, the rate constant describing radioactivity elimination from the right lung (k E,lung ) and the area under the curve (AUC lung ) were calculated from 0 to 5 min after start of the PET scan as measures of pulmonary MRP1 activity. Co-administration of MK571 resulted in a pronounced decrease in k E,lung (25-fold, p < 0.0001) and an increase in AUC lung (5.3-fold, p < 0.0001) when compared with vehicle-treated animals. In contrast, in budesonide-treated animals k E,lung and AUC lung were not significantly different from the vehicle group. Our results show that i.t. aerosolized budesonide at an approximately 5 times higher dose than the maximum clinical dose leads to no change in pulmonary MRP1 activity, suggesting a lack of an effect of inhaled budesonide treatment on the MRP1-mediated cellular detoxifying capacity of the lungs. However, the strong effect observed for MK571 raises the possibility for the occurrence of transporter-mediated drug-drug interactions at the pulmonary epithelium with inhaled medicines., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

In the lungs, the membrane transporter P-glycoprotein (P-gp) is expressed in the apical (i.e. lumen-facing) membrane of airway epithelial cells and in the luminal (blood-facing) membrane of pulmonary capillary endothelial cells. To better understand the influence of P-gp on the pulmonary disposition of inhaled P-gp substrate drugs, we measured the intrapulmonary pharmacokinetics of the intratracheally (i.t.) aerosolized model P-gp substrate [ 11 C]metoclopramide in presence and absence of P-gp activity by means of positron emission tomography (PET) imaging in rats. Data were compared to data previously acquired with the model P-gp substrates (R)-[ 11 C]verapamil and [ 11 C]N-desmethyl-loperamide, using the same experimental set-up. Groups of wild-type rats, either untreated or treated with the P-gp inhibitor tariquidar, and Abcb1a/b (-/-) rats underwent 90-min dynamic PET scans after i.t. aerosolization of [ 11 C]metoclopramide. Lung exposure to [ 11 C]metoclopramide was expressed as the area under the right lung concentration-time curve (AUC lung ). AUC lung values were significantly higher in Abcb1a/b (-/-) rats (1.8-fold, p ≤ 0.0001) and in tariquidar-treated wild-type rats (1.6-fold, p ≤ 0.01) than in untreated wild-type rats. This differed from previously obtained results with (R)-[ 11 C]verapamil and [ 11 C]N-desmethyl-loperamide, which showed decreased exposure in the rat lung in absence of P-gp activity. Our results suggest that transepithelial transfer of [ 11 C]metoclopramide was not or only to a small extent affected by P-gp activity, presumably due to the compound's high passive permeability. The increased lung retention of [ 11 C]metoclopramide may be due to decreased P-gp-mediated clearance into the blood in absence of P-gp activity in capillary endothelial cells. The overall effect of P-gp on the lung exposure to inhaled P-gp substrate drugs may, thus, be determined by a balance of opposing effects at the pulmonary epithelium and endothelium., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [ 18 F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [ 18 F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CL renal ) of [ 18 F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CL renal was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [ 18 F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [ 18 F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.

Purpose: Nanodiamonds (NDs) represent a new class of nanoparticles and have gained increasing interest in medical applications. Modifying the surface coating by attaching binding ligands or imaging probes can transform NDs into multi-modal targeting probes. This study evaluated the biokinetics and biodistribution of 68 Ga-radiolabelled NDs in a xenograft model., Procedures: NDs were coated with an albumin-derived copolymer modified with desferrioxamine to provide a chelator for radiolabeling. In vivo studies were conducted in AR42J tumor-bearing CD1 mice to evaluate biodistribution and tumor accumulation of the NDs., Results: Coated NDs were successfully radiolabeled using 68 Ga at room temperature with radiolabeling efficiencies up to 91.8 ± 3.2 % as assessed by radio-TLC. In vivo studies revealed the highest accumulation in the liver and spleen, whereas tumor radioactivity concentration was low., Conclusions: Radiolabeling of coated NDs could be achieved. However, the obtained results indicate these coated NDs' limitations in their biodistribution within the conducted studies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of lung epithelial cells. To assess the influence of P-gp and BCRP on the pulmonary disposition of inhaled drugs, we performed positron emission tomography (PET) imaging in rats after intratracheal aerosolization of two model P-gp/BCRP substrate radiotracers (i.e. [ 11 C]erlotinib and [ 11 C]tariquidar). We studied rat groups in which both transporters were active (i.e. wild-type rats), either of the two transporters was inactive (Abcb1a/b (-/-) and Abcg2 (-/-) rats) or both transporters were inactive (Abcg2 (-/-) rats in which pulmonary P-gp activity was inhibited by treatment with unlabeled tariquidar). PET-measured lung distribution data were compared with brain-to-plasma radioactivity concentration ratios measured in a gamma counter at the end of the PET scan. For [ 11 C]erlotinib, lung exposure (AUC lungs ) was moderately but not significantly increased in Abcb1a/b (-/-) rats (1.6-fold) and Abcg2 (-/-) rats (1.5-fold), and markedly (3.6-fold, p < 0.0001) increased in tariquidar-treated Abcg2 (-/-) rats, compared to wild-type rats. Similarly, the brain uptake of [ 11 C]erlotinib was substantially (4.5-fold, p < 0.0001) increased when both P-gp and BCRP activities were impaired. For [ 11 C]tariquidar, differences in AUC lungs between groups pointed into a similar direction as for [ 11 C]erlotinib, but were less pronounced and lacked statistical significance. Our study demonstrates functional P-gp and BCRP activity in vivo in the lungs and further suggests functional redundancy between P-gp and BCRP in limiting the pulmonary uptake of a model P-gp/BCRP substrate, analogous to the blood-brain barrier. Our results suggest that pulmonary efflux transporters are important for the efficacy and safety of inhaled drugs and that their modulation may be exploited in order to improve the pharmacokinetic and pharmacodynamic performance of pulmonary delivered drugs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lassa fever is an acute viral haemorrhagic disease caused by the Lassa virus (LASV). It is endemic in West Africa and infects about 300,000 people each year, leading to approximately 5000 deaths annually. The development of the LASV vaccine has been listed as a priority by the World Health Organization since 2018. Considering the accelerated development and availability of vaccines against COVID-19, we set out to assess the prospects of LASV vaccines and the progress made so far., Materials and Methods: We reviewed the progress made on twenty-six vaccine candidates listed by Salami et al . (2019) and searched for new vaccine candidates through Google Scholar, PubMed, and DOAJ from June to July 2021. We searched the articles published in English using keywords that included "vaccine" AND "Lassa fever" OR "Lassa virus" in the title/abstract., Results: Thirty-four candidate vaccines were identified - 26 already listed in the review by Salami et al. and an additional 8, which were developed over the last seven years. 30 vaccines are still in the pre-clinical stage while 4 of them are currently undergoing clinical trials. The most promising candidates in 2019 were vesicular stomatitis virus-vectored vaccine and live-attenuated MV/LASV vaccine; both had progressed to clinical trials., Conclusions: Despite the focus on COVID-19 vaccines since 2020, LASV vaccine is under development and continues to make impressive progress, hence more emphasis should be put into exploring further clinical studies related to the most promising types of vaccines identified., (Copyright: © 2022 Afr. J. Infect. Diseases.)

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[ 11 C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1 (-/-) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity ( k elim ) was calculated from time-activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.

Several drugs approved for inhalation for the treatment of pulmonary diseases are substrates of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (P-gp). P-gp is expressed in the apical membrane of pulmonary epithelial cells and could play a role in modulating the pulmonary absorption and distribution of inhaled drugs, thereby potentially contributing to variability in therapeutic response and/or systemic side effects. We developed a new in vivo experimental approach to assess the functional impact of P-gp on the pulmonary delivery of inhaled drugs in rats. By using positron emission tomography (PET) imaging, we measured the intrapulmonary pharmacokinetics of the model P-gp substrates (R)-[ 11 C]verapamil ([ 11 C]VPM) and [ 11 C]-N-desmethyl-loperamide ([ 11 C]dLOP) administered by intratracheal aerosolization in three rat groups: wild-type, Abcb1a/b (-/-) and wild-type treated with the P-gp inhibitor tariquidar. Lung exposure (AUC lung&#95;right ) to [ 11 C]VPM was 64% and 50% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b (-/-) rats, respectively, compared to untreated wild-type rats. For [ 11 C]dLOP, AUC lung&#95;right was 59% and 34% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b (-/-) rats, respectively. Our results show that P-gp can affect the pulmonary disposition of inhaled P-gp substrates, whereby a decrease in P-gp activity may lead to lower lung exposure and potentially to a decrease in therapeutic efficacy. Our study highlights the potential of PET imaging with intratracheally aerosolized radiotracers to assess the impact of membrane transporters on pulmonary drug delivery, in rodents and potentially also in humans., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Training of the innate immune system with orally ingested bacterial extracts was demonstrated to have beneficial effects on infection clearance and disease outcome. The aim of our study was to identify cellular and molecular processes responsible for these immunological benefits. We used a murine coronavirus (MCoV) A59 mouse model treated with the immune activating bacterial extract Broncho-Vaxom (BV) OM-85. Tissue samples were analysed with qPCR, RNA sequencing, histology, and flow cytometry. After BV OM-85 treatment, interstitial macrophages accumulated in lung tissue leading to a faster response of type I interferon (IFN) signalling after MCoV infection resulting in overall lung tissue protection. Moreover, RNA sequencing showed that lung tissue from mice receiving BV OM-85 resembled an intermediate stage between healthy and viral infected lung tissue at day 4, indicating a faster return to normal tissue homoeostasis. The pharmacologic effect was mimicked by adoptively transferring naive lung macrophages into lungs from recipient mice before virus infection. The beneficial effect of BV OM-85 was abolished when inhibiting initial type I IFN signalling. Overall, our data suggest that BV OM-85 enhances lung macrophages allowing for a faster IFN response towards a viral challenge as part of the oral-induced innate immune system training., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: To better understand the etiology and pathomechanisms of Alzheimer's disease, several transgenic animal models that overexpress human tau or human amyloid-beta (Aβ) have been developed. In the present study, we generated a novel transgenic rat model by cross-breeding amyloid precursor protein (APP) rats with tau rats. We characterized this model by performing positron emission tomography scans combined with immunofluorescent labeling and cerebrospinal fluid analyses., Methods: APP/Tau rats were generated by cross-breeding male McGill-R-Thy1-APP transgenic rats with female hTau-40/P301L transgenic rats. APP/Tau double transgenic rats and non-transgenic (ntg) littermates aged 7, 13, and 21 months were subjected to dynamic [ 11 C] PiB scan and dynamic [ 18 F]THK-5317 scans. For regional brain analysis, a template was generated from anatomical MR images of selected animals, which was co-registered with the PET images. Regional analysis was performed by application of the simplified reference tissue model ([ 11 C]PiB data), whereas [ 18 F]THK-5317 data were analyzed using a 2-tissue compartment model and Logan graphical analysis. In addition, immunofluorescent labeling (tau, amyloid) and cerebrospinal fluid analyses were performed., Results: [ 11 C]PiB binding potential (BP ND ) and [ 18 F]THK-5317 volume of distribution (V T ) showed an increase with age in several brain regions in the APP/Tau group but not in the ntg control group. Immunohistochemical analysis of brain slices of PET-scanned animals revealed a positive correlation between Aβ labeling and [ 11 C]PiB regional BP ND . Tau staining yielded a trend towards higher levels in the cortex and hippocampus of APP/Tau rats compared with ntg littermates, but without reaching statistical significance. No correlation was found between tau immunofluorescence labeling results and the respective [ 18 F]THK-5317 V T values., Conclusions: We thoroughly characterized a novel APP/Tau rat model using combined PET imaging and immunofluorescence analysis. We observed an age-related increase in [ 11 C]PiB and [ 18 F]THK-5317 binding in several brain regions in the APP/Tau group but not in the ntg group. Although we were able to reveal a positive correlation between amyloid labeling and [ 11 C]PiB regional brain uptake, we observed relatively low human tau and amyloid fibril expression levels and a somewhat unstable brain pathology which questions the utility of this animal model for further studies., (© 2021. The Author(s).)

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood-brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [ 11 C]tariquidar, [ 11 C]erlotinib, and [ 11 C]elacridar to assess whether a similar functional redundancy as at the BBB exists in the liver, where both transporters mediate the biliary excretion of drugs. Wild-type, Abcb1a/b (-/-) , Abcg2 (-/-) , and Abcb1a/b (-/-) Abcg2 (-/-) mice underwent dynamic whole-body PET scans after i.v. injection of either [ 11 C]tariquidar, [ 11 C]erlotinib, or [ 11 C]elacridar. Brain uptake of all three radiotracers was markedly higher in Abcb1a/b (-/-) Abcg2 (-/-) mice than in wild-type mice, while only moderately changed in Abcb1a/b (-/-) and Abcg2 (-/-) mice. The transfer of radioactivity from liver to excreted bile was significantly lower in Abcb1a/b (-/-) Abcg2 (-/-) mice and almost unchanged in Abcb1a/b (-/-) and Abcg2 (-/-) mice (with the exception of [ 11 C]erlotinib, for which biliary excretion was also significantly reduced in Abcg2 (-/-) mice). Our data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P-gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level.

Ciprofloxacin is a commonly prescribed fluoroquinolone antibiotic which is cleared by active tubular secretion and intestinal excretion. Ciprofloxacin is a known substrate of the ATP-binding cassette (ABC) transporters breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). In this work, we used positron emission tomography (PET) imaging to investigate the influence of BCRP, MRP4, MRP2 and P-glycoprotein (P-gp) on the excretion of [ 18 F]ciprofloxacin in mice. Dynamic 90-min PET scans were performed after intravenous injection of [ 18 F]ciprofloxacin in wild-type mice without and with pre-treatment with the broad-spectrum MRP inhibitor MK571. Moreover, [ 18 F]ciprofloxacin PET scans were performed in Abcc4 (-/-) , Abcc2 (-/-) , Abcc4 (-/-) Abcg2 (-/-) and Abcb1a/b (-/-) Abcg2 (-/-) mice. In addition to non-compartmental pharmacokinetic (PK) analysis, a novel three-compartment PK model was developed for a detailed assessment of the renal disposition of [ 18 F]ciprofloxacin. In MK571 pre-treated mice, a significant increase in the blood exposure to [ 18 F]ciprofloxacin was observed along with a significant reduction in the renal and intestinal clearances. PK modelling revealed a significant reduction in renal radioactivity uptake (CL 1 ) and in the rate constants for transfer of radioactivity from the corticomedullary renal region into blood (k 2 ) and urine (k 3 ), respectively, after MK571 administration. No changes in the renal clearance or in the estimated kidney PK model parameters were observed in any of the studied knockout models, while a significant reduction in the intestinal clearance was observed in Abcc2 (-/-) and Abcc4 (-/-) Abcg2 (-/-) mice. Our data failed to reveal a role of any of the studied ABC transporters in the tubular secretion of ciprofloxacin. This may indicate that ciprofloxacin is handled in the kidneys by more than one transporter family, most likely with a great degree of mutual functional redundancy. Our study highlights the potential of PET imaging for an assessment of transporter-mediated renal excretion of radiolabelled drugs., (Copyright © 2021. Published by Elsevier B.V.)

P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood-brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [ 11 C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [ 11 C]erlotinib was low (brain distribution volume, V T,brain  < 0.3 mL/cm 3 ). Co-infusion of erlotinib and tariquidar increased V T,brain in mice by 3.0-fold and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar alone led to less pronounced V T,brain increases in both species. Treatment of cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly targeted anticancer drugs for a more effective treatment of brain tumors.

Adenosine (Ado) is an important signaling molecule involved in stress responses. Studies in mammalian models have shown that Ado regulates signaling mechanisms involved in "danger-sensing" and tissue-protection. Yet, little is known about the role of Ado signaling in Drosophila . In the present study, we observed lower extracellular Ado concentration and suppressed expression of Ado transporters in flies expressing mutant huntingtin protein (mHTT). We altered Ado signaling using genetic tools and found that the overexpression of Ado metabolic enzymes, as well as the suppression of Ado receptor (AdoR) and transporters (ENTs), were able to minimize mHTT-induced mortality. We also identified the downstream targets of the AdoR pathway, the modifier of mdg4 (Mod(mdg4)) and heat-shock protein 70 (Hsp70), which modulated the formation of mHTT aggregates. Finally, we showed that a decrease in Ado signaling affects other Drosophila stress reactions, including paraquat and heat-shock treatments. Our study provides important insights into how Ado regulates stress responses in Drosophila ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lin, Maaroufi, Kucerova, Rouhova, Filip and Zurovec.)

Purpose: To investigate the role of cation transporters (OCTs, MATEs) in the renal and hepatic disposition of the radiolabeled antiemetic drug [ 11 C]metoclopramide in mice with PET., Methods: PET was performed in wild-type mice after administration of an intravenous microdose (<1 μg) of [ 11 C]metoclopramide without and with co-administration of either unlabeled metoclopramide (5 or 10 mg/kg) or the prototypical cation transporter inhibitors cimetidine (150 mg/kg) or sulpiride (25 mg/kg). [ 11 C]Metoclopramide PET was also performed in wild-type and Slc22a1/2 (-/-) mice. Radiolabeled metabolites were measured at 15 min after radiotracer injection and PET data were corrected for radiolabeled metabolites., Results: [ 11 C]Metoclopramide was highly metabolized and [ 11 C]metoclopramide-derived radioactivity was excreted into the urine. The different investigated treatments decreased (~2.5-fold) the uptake of [ 11 C]metoclopramide from plasma into the kidney and liver, inhibited metabolism and decreased (up to 3.8-fold) urinary excretion, which resulted in increased plasma concentrations of [ 11 C]metoclopramide. Kidney and liver uptake were moderately (~1.3-fold) reduced in Slc22a1/2 (-/-) mice., Conclusions: Our results suggest a contribution of OCT1/2 to the kidney and liver uptake and of MATEs to the urinary excretion of [ 11 C]metoclopramide in mice. Cation transporters may contribute, next to variability in the activity of metabolizing enzymes, to variability in metoclopramide pharmacokinetics and side effects.

Background: Endoscopic saphenous vein harvesting (EVH) for coronary artery bypass grafting (CABG) has been developed to reduce leg wound problems. This study was undertaken to evaluate postoperative complications and patient's subjective satisfaction comparing EVH and surgical vein harvesting (SVH)., Methods: From January to December 2017, patients undergoing elective cardiac surgery (CABG, CABG + Valve repair or replacement) underwent saphenous vein graft harvesting either by EVH ( n  = 136) or SVH ( n  = 104). Clinical follow-up was scheduled for day 7 and > 45 days after surgery. Primary end points were divided into two subgroups. The first one included postoperative extent of subjective pain and satisfaction with the cosmetic results described by the patients themselves, while the second subgroup included objective postoperative complications including wound healing disturbances, hematoma, and neuropathy. Secondary end point was length of hospital stay., Results: At 7 days follow-up, EVH patients were more satisfied with the cosmetic results than those of the SVH group ( p  < 0.001) and expressed a significant tendency toward lower subjective pain compared with the SVH patients ( p  < 0.001), exhibited significantly lower cellulitis ( p -0.002), neuropathy ( p -0.005), and superficial wound healing disturbance ( p -0.007). During further follow-up at > 45 days, patients with EVH were still more satisfied with the cosmetic results ( p  < 0.001) and expressed lower subjective pain ( p  < 0.001), while the other objective wound parameters did not show significant differences between both groups. Mean length of hospital stay of EVH patients was 0.7 days less compared with SVH patients., Conclusions: Our findings demonstrate the noninferiority of EVH in the short term and in the early medium term., Competing Interests: Mrs Rudolph discloses that she has a financial relationship with company Maquet GmbH; all other authors declare that there is no conflict of interest., (Thieme. All rights reserved.)

Background: ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) are co-localized at the blood-brain barrier (BBB), where they restrict the brain distribution of many different drugs. Moreover, ABCB1 and possibly ABCG2 play a role in Alzheimer's disease (AD) by mediating the brain clearance of beta-amyloid (Aβ) across the BBB. This study aimed to compare the abundance and activity of ABCG2 in a commonly used β-amyloidosis mouse model (APP/PS1-21) with age-matched wild-type mice., Methods: The abundance of ABCG2 was assessed by semi-quantitative immunohistochemical analysis of brain slices of APP/PS1-21 and wild-type mice aged 6 months. Moreover, the brain distribution of two dual ABCB1/ABCG2 substrate radiotracers ([ 11 C]tariquidar and [ 11 C]erlotinib) was assessed in APP/PS1-21 and wild-type mice with positron emission tomography (PET). [ 11 C]Tariquidar PET scans were performed without and with partial inhibition of ABCG2 with Ko143, while [ 11 C]erlotinib PET scans were only performed under baseline conditions., Results: Immunohistochemical analysis revealed a significant reduction (by 29-37%) in the number of ABCG2-stained microvessels in the brains of APP/PS1-21 mice. Partial ABCG2 inhibition significantly increased the brain distribution of [ 11 C]tariquidar in APP/PS1-21 and wild-type mice, but the brain distribution of [ 11 C]tariquidar did not differ under both conditions between the two mouse strains. Similar results were obtained with [ 11 C]erlotinib., Conclusions: Despite a reduction in the abundance of cerebral ABCG2 and ABCB1 in APP/PS1-21 mice, the brain distribution of two dual ABCB1/ABCG2 substrates was unaltered. Our results suggest that the brain distribution of clinically used ABCB1/ABCG2 substrate drugs may not differ between AD patients and healthy people.

Multidrug resistance-associated protein 1 (adenosine triphosphate-binding cassette subfamily C member 1 [ABCC1]) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. The aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7- 11 C-methylpurine ( 11 C-BMP), a prodrug radiotracer that is intracellularly conjugated with glutathione to form the ABCC1 substrate S -(6-(7- 11 C-methylpurinyl))glutathione ( 11 C-MPG). Methods: Groups of Abcc1 (-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571, and wild-type control rats underwent dynamic PET scans after administration of 11 C-BMP intravenously or by intratracheal aerosolization. In vitro transport experiments were performed with unlabeled BMP on the human distal lung epithelial cell line NCI-H441. Results: The pulmonary kinetics of radioactivity significantly differed between wild-type and Abcc1 (-/-) rats, but differences were more pronounced after intratracheal than after intravenous administration. After intravenous administration, lung exposure (area under the lung time-activity curve from 0 to 80 min after radiotracer administration [AUC lung ]) was 77% higher and the elimination slope of radioactivity washout from the lungs ( k E,lung ) was 70% lower in Abcc1 (-/-) rats, whereas after intratracheal administration, AUC lung was 352% higher and k E,lung was 86% lower in Abcc1 (-/-) rats. Pretreatment with MK571 decreased k E,lung by 20% after intratracheal radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in the presence than in the absence of MK571. Conclusion: PET with pulmonary administered 11 C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms, or concomitant drug intake on pulmonary ABCC1 activity., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood-brain barrier (BBB) in promoting clearance of neurotoxic β-amyloid (Aβ) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aβ deposits in the brain by enhancing clearance of Aβ peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer 11 C-metoclopramide can measure ABCB1 induction at the BBB in a β-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 d underwent 11 C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 d. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aβ levels. In separate groups of mice, radiolabeled metabolites of 11 C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain ( k E,brain ) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in k E,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aβ levels. There was a significant positive correlation between k E,brain and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in k E,brain was found. Metabolite analysis showed that most radioactivity in the brain comprised unmetabolized 11 C-metoclopramide in all animal groups. Conclusion: 11 C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in Alzheimer disease patients to noninvasively evaluate strategies to enhance the clearance properties of the BBB., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Previous data suggest a possible link between multidrug resistance-associated protein 1 (ABCC1) and brain clearance of beta-amyloid (Aβ). We used PET with 6-bromo-7-[ 11 C]methylpurine ([ 11 C]BMP) to measure cerebral ABCC1 transport activity in a beta-amyloidosis mouse model (APP/PS1-21) and in wild-type mice aged 50 and 170 days, without and with pretreatment with the ABCC1 inhibitor MK571. One hundred seventy days-old-animals additionally underwent [ 11 C]PiB PET scans to measure Aβ load. While baseline [ 11 C]BMP PET scans detected no differences in the elimination slope of radioactivity washout from the brain (k elim ) between APP/PS1-21 and wild-type mice of both age groups, PET scans after MK571 pretreatment revealed significantly higher k elim values in APP/PS1-21 mice than in wild-type mice aged 170 days, suggesting increased ABCC1 activity. The observed increase in k elim occurred across all investigated brain regions and was independent of the presence of Aβ plaques measured with [ 11 C]PiB. Western blot analysis revealed a trend towards increased whole brain ABCC1 levels in 170 days-old-APP/PS1-21 mice versus wild-type mice and a significant positive correlation between ABCC1 levels and k elim . Our data point to an upregulation of ABCC1 in APP/PS1-21 mice, which may be related to an induction of ABCC1 in astrocytes as a protective mechanism against oxidative stress.

Introduction: Tau deposition is one of the hallmarks of Alzheimer's disease (AD) and can be visualized and quantified using [ 18 F]THK-5317 together with kinetic modeling. To determine the feasibility of this approach, we measured blood/plasma pharmacokinetics and radiotracer metabolism in female and male rats., Methods: Female and male rats (n = 11-12) were cannulated via the femoral artery for continuous blood sampling. Blood sampling was performed at regular intervals after intravenous injection of [ 18 F]THK-5317. After collection of the last blood sample, animals were sacrificed, and organs were excised. Blood from minute 5, 20 and 60 was centrifuged to obtain plasma. Radiolabeled metabolites in plasma, brain, liver and urine were analyzed by radio-thin-layer chromatography (radio-TLC)., Results: Plasma pharmacokinetics and metabolism were significantly different between female and male rats. [ 18 F]THK-5317 plasma clearance was faster in female (0.66 ± 0.08 mL/h/kg BW) than in male (0.52 ± 0.11 mL/h/kg BW) rats (p = .005). The percentage of unmetabolized parent was significantly different between both sexes at 20 min and 60 min p.i. In the liver, a 1.6-fold higher radioactivity concentration was found in male versus female animals and in addition also the percentage of unmetabolized parent was different., Conclusion: Our results show pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [ 18 F]THK-5317 in rats. Female animals showed a faster plasma clearance compared to males. These results underline the importance of investigating both sexes and also support the notion that individual input functions or sex-specific population-based input functions are needed for kinetic modeling analyses., Advances in Knowledge: First preclinical study in rats showing pronounced sex differences in blood/plasma pharmacokinetics and metabolism of [ 18 F]THK-5317., Implications for Patient Care: Sex-specific differences might also be present in humans and thus clinical trials should have adequate sample size to account for effects in men and women separately., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

P-glycoprotein (P-gp, ABCB1) is an efflux transporter at the blood-brain barrier (BBB), which mediates clearance of beta-amyloid (Aβ) from brain into blood. We used ( R )-[ 11 C]verapamil PET in combination with partial P-gp inhibition with tariquidar to measure cerebral P-gp function in a beta-amyloidosis mouse model (APPtg) and in control mice at three different ages (50, 200 and 380 days). Following tariquidar pre-treatment (4 mg/kg), whole brain-to-plasma radioactivity concentration ratios ( K p,brain ) were significantly higher in APPtg than in wild-type mice aged 50 days, pointing to decreased cerebral P-gp function. Moreover, we found an age-dependent decrease in cerebral P-gp function in both wild-type and APPtg mice of up to -50%. Alterations in P-gp function were more pronounced in Aβ-rich brain regions (hippocampus, cortex) than in a control region with negligible Aβ load (cerebellum). PET results were confirmed by immunohistochemical staining of P-gp in brain microvessels. Our results confirm previous findings of reduced P-gp function in Alzheimer's disease mouse models and show that our PET protocol possesses adequate sensitivity to measure these functional changes in vivo. Our PET protocol may find use in clinical studies to test the efficacy of drugs to induce P-gp function at the human BBB to enhance Aβ clearance.

Background:  Endocarditis remains one of the most threatening diagnoses in cardiac surgery and is still increasing. Particularly, device-related as well as prosthetic endocarditis appears to be on the rise. Early mortality and periprocedural complications are high jeopardizing the success of surgical efforts. We looked at the development of the numbers and the distribution of endocarditis in an all-comer analysis., Methods:  From 2003 to 2017, 752 patients with endocarditis were transferred to our cardiosurgical institution (mean age 65 ± 13 years; mean logistic EuroSCORE 28.01%; males 74.33%). A total of 89.49% of them were surgically treated; 30.01% redo cases thereof; and 9.17% had been operated previously for acute endocarditis., Results:  While the total number of cardiosurgical procedures remained relatively stable throughout the years, 20 patients were admitted in 2003 and 79 in 2017 yielding more than fourfold increase ( p  < 0.001). Early mortality of all patients was 25.1%. Septic emboli occurred in 23.7% and 43.8% cerebral emboli thereof. A significant increase of aortic, mitral, and tricuspid valves involvement was observed ( p  < 0.001). An increase of device-related endocarditis was also noted ( p  < 0.001)., Conclusion:  Endocarditis remains a serious problem with high early mortality and morbidity. The vast increase of electrophysiological device implantations has resulted in an increase of tricuspid valve involvement. Liberalization of endocarditis prophylaxis, that is, more restrictive use of antibiotics in 2007 may have at least partially contributed to an increase of the individual risk to suffer from acute endocarditis. A renaissance of a stricter endocarditis-prophylaxis may thus be considered., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Multidrug resistance-associated proteins (MRPs) mediate the hepatobiliary and renal excretion of many drugs and drug conjugates. The positron emission tomography (PET) tracer 6-bromo-7-[ 11 C]methylpurine is rapidly converted in tissues by glutathione-S-transferases into its glutathione conjugate, and has been used to measure the activity of Abcc1 in the brain and the lungs of mice. Aim of this work was to investigate if the activity of MRPs in excretory organs can be measured with 6-bromo-7-[ 11 C]methylpurine., Procedures: We performed PET scans with 6-bromo-7-[ 11 C]methylpurine in groups of wild-type, Abcc4 (-/-) and Abcc1 (-/-) mice, with and without pre-treatment with the prototypical MRP inhibitor MK571., Results: 6-Bromo-7-[ 11 C]methylpurine-derived radioactivity predominantly underwent renal excretion. In blood, MK571 treatment led to a significant increase in the AUC and a decrease in the elimination rate constant of radioactivity (k elimination,blood ). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (k uptake,kidney ), k elimination,kidney , and the rate constant for tubular secretion of radioactivity (k urine ). Experiments in Abcc4 (-/-) mice indicated that Abcc4 contributed to renal excretion of 6-bromo-7-[ 11 C]methylpurine-derived radioactivity., Conclusions: Our data suggest that 6-bromo-7-[ 11 C]methylpurine may be useful to assess the activity of MRPs in the kidneys as well as in other organs (brain, lungs), although further work is needed to identify the MRP subtypes involved in the disposition of 6-bromo-7-[ 11 C]methylpurine-derived radioactivity.

P-Glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters at the blood-brain barrier (BBB), which effectively restrict brain distribution of diverse drugs, such as tyrosine kinase inhibitors. There is a crucial need for pharmacological ABCB1 and ABCG2 inhibition protocols for a more effective treatment of brain diseases. In the present study, seven marketed drugs (osimertinib, erlotinib, nilotinib, imatinib, lapatinib, pazopanib, and cyclosporine A) and one nonmarketed drug (tariquidar), with known in vitro ABCB1/ABCG2 inhibitory properties, were screened for their inhibitory potency at the BBB in vivo. Positron emission tomography (PET) using the model ABCB1/ABCG2 substrate [ 11 C]erlotinib was performed in mice. Tested inhibitors were administered as i.v. bolus injections at 30 min before the start of the PET scan, followed by a continuous i.v. infusion for the duration of the PET scan. Five of the tested drugs increased total distribution volume of [ 11 C]erlotinib in the brain ( V T,brain ) compared to vehicle-treated animals (tariquidar, + 69%; erlotinib, + 19% and +23% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 22%; lapatinib, + 25%; and cyclosporine A, + 49%). For all drugs, increases in [ 11 C]erlotinib brain distribution were lower than in Abcb1a/b (-/-) Abcg2 (-/-) mice (+149%), which suggested that only partial ABCB1/ABCG2 inhibition was reached at the mouse BBB. The plasma concentrations of the tested drugs at the time of the PET scan were higher than clinically achievable plasma concentrations. Some of the tested drugs led to significant increases in blood radioactivity concentrations measured at the end of the PET scan (erlotinib, + 103% and +113% for the 21.5 mg/kg and the 43 mg/kg dose, respectively; imatinib, + 125%; and cyclosporine A, + 101%), which was most likely caused by decreased hepatobiliary excretion of radioactivity. Taken together, our data suggest that some marketed tyrosine kinase inhibitors may be repurposed to inhibit ABCB1 and ABCG2 at the BBB. From a clinical perspective, moderate increases in brain delivery despite the administration of high i.v. doses as well as peripheral drug-drug interactions due to transporter inhibition in clearance organs question the translatability of this concept.

Ko143 is a reference inhibitor of the adenosine triphosphate-binding cassette (ABC) transporter breast cancer resistance protein (humans: ABCG2, rodents: Abcg2) for in vitro and in vivo use. Previous in vitro data indicate that Ko143 binds specifically to ABCG2/Abcg2, suggesting a potential utility of Ko143 as a positron emission tomography (PET) tracer to assess the density (abundance) of ABCG2 in different tissues. In this work we radiolabeled Ko143 with carbon-11 ( 11 C) and performed small-animal PET experiments with [ 11 C]Ko143 in wild-type, Abcg2 (-/-) , Abcb1a/b (-/-) and Abcb1a/b (-/-) Abcg2 (-/-) mice to assess the influence of Abcg2 and Abcb1a/b on tissue distribution and excretion of [ 11 C]Ko143. [ 11 C]Ko143 was extensively metabolized in vivo and unidentified radiolabeled metabolites were found in all investigated tissues. We detected no significant differences between wild-type and Abcg2 (-/-) mice in the distribution of [ 11 C]Ko143-derived radioactivity to Abcg2-expressing organs (brain, liver and kidney). [ 11 C]Ko143 and possibly its radiolabeled metabolites were transported by Abcb1a and not by Abcg2 at the mouse blood-brain barrier. [ 11 C]Ko143-derived radioactivity underwent both hepatobiliary and urinary excretion, with Abcg2 playing a possible role in mediating the transport of radiolabeled metabolites of [ 11 C]Ko143 from the kidney into urine. Experiments in which a pharmacologic dose of unlabeled Ko143 (10 mg/kg) was co-administered with [ 11 C]Ko143 revealed pronounced effects of the vehicle used for Ko143 formulation (containing polyethylene glycol 300 and polysorbate 80) on radioactivity distribution to the brain and the liver, as well as on hepatobiliary and urinary excretion of radioactivity. Our results highlight the challenges associated with the development of PET tracers for ABC transporters and emphasize that inhibitory effects of pharmaceutical excipients on membrane transporters need to be considered when performing in vivo drug-drug interaction studies. Finally, our study illustrates the power of small-animal PET to assess the interaction of drug molecules with membrane transporters on a whole body level., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Flies, worms, yeast and more recently zebra fish have all been engineered to express expanded polyglutamine repeat versions of Huntingtin with various resulting pathologies including early death, neurodegeneration, and loss of motor function. Each of these models present particular features that make it useful in studying the mechanisms of polyglutamine pathology. However, one particular unbiased readout of mHTT pathology is functional loss of motor control. Loss of motor control is prominent in patients, but it remains unresolved whether pathogenic symptoms in patients result from overt degeneration and loss of neurons or from malfunctioning of surviving neurons as the pathogenic insult builds up. This is why a functional assay such as motor control can be uniquely powerful in revealing early as well as late neurological deficits and does not rely on assumptions such as that the level of inclusions or the degree of neuronal loss can be equated with the level of pathology. Drosophila is well suited for such assays because it contains a functioning nervous system with many parallels to the human condition. In addition, the ability to readily express mHTT transgenes in different tissues and subsets of neurons allows one the possibility of isolating a particular effect to a subset of neurons where one can correlate subcellular events in response to mHTT challenge with pathology at both the cellular and organismal levels. Here we describe methods to monitor the degree of motor function disruption in Drosophila models of HD and we include a brief summary of other nonmammalian models of HD and discussion of their unique strengths.

Introduction: [ 11 C]Erlotinib PET has shown promise to distinguish non-small cell lung cancer (NSCLC) tumors harboring the activating epidermal growth factor receptor (EGFR) mutation delE746-A750 from tumors with wild-type EGFR. To assess the suitability of [ 11 C]erlotinib PET to detect the emergence of acquired erlotinib resistance in initially erlotinib-responsive tumors, we performed in vitro binding and PET experiments in mice bearing tumor xenografts using a range of different cancer cells, which were erlotinib-sensitive or exhibited clinically relevant resistance mechanisms to erlotinib., Methods: The following cell lines were used for in vitro binding and PET experiments: the epidermoid carcinoma cell line A-431 (erlotinib-sensitive, wild-type EGFR) and the three NSCLC cell lines HCC827 (erlotinib-sensitive, delE746-A750), HCC827 EPR (erlotinib-resistant, delE746-A750 and T790M) and HCC827 ERLO (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [ 11 C]erlotinib PET scans, a baseline scan and a second scan in which unlabeled erlotinib (10mg/kg) was co-injected. Logan graphical analysis was used to estimate total distribution volume (V T ) of [ 11 C]erlotinib in tumors., Results: In vitro experiments revealed significantly higher uptake of [ 11 C]erlotinib (5.2-fold) in the three NSCLC cell lines as compared to A-431 cells. In all four cell lines co-incubation with unlabeled erlotinib (1μM) led to significant reductions in [ 11 C]erlotinib uptake (-19% to -66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral [ 11 C]erlotinib V T values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral V T was significantly reduced following co-injection of unlabeled erlotinib (-20% to -35%)., Conclusions: We found no significant differences in the in vitro and in vivo binding of [ 11 C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [ 11 C]erlotinib PET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In recent years, radiofluorinated alkyl azides have been reported for click radiolabeling and pretargeted PET imaging, but only little is known about the biodistribution and metabolism of these compounds. In this work, we present a significantly improved procedure for the synthesis of [ 18 F]fluoroethyl azide and reinvestigated this radiolabeled probe in detail showing poor stability and very restricted suitability for in vivo application. Therefore, modified low-molecular-weight [ 18 F]fluoroalkyl azides were developed. Propargyl-tagged endomorphin-1 (as model compound) was successfully radiolabeled in high yield and short reaction time making these probes useful and efficient bioorthogonal tools for rapid radiolabeling. Biodistribution, pharmacokinetics and in vivo stability were studied by preclinical PET/MR scanning and metabolite analysis. The results of this study revealed only limited applicability of [ 18 F]fluoroalkyl azides for in vivo application.

Introduction: In recent years extra-corporal application of boron neutron capture therapy (BNCT) was evaluated for liver primary tumors or liver metastases. A prerequisite for such a high-risk procedure is proof of preferential delivery and high uptake of a 10 B-pharmaceutical in liver malignancies. In this work we evaluated in a preclinical tumor model if [ 18 F]FBPA tissue distribution measured with PET is able to predict the tissue distribution of [ 10 B]L-BPA., Methods: Tumor bearing mice (hepatocellular carcinoma cell line, HuH-7) were either subject of a [ 18 F]FBPA-PET scan with subsequent measurement of radioactivity content in extracted organs using a gamma counter or injected with [ 10 B]L-BPA with tissue samples analyzed by prompt gamma activation analysis (PGAA) or quantitative neutron capture radiography (QNCR). The impact of L-tyrosine, L-DOPA and L-BPA preloading on the tissue distribution of [ 18 F]FBPA and [ 10 B]L-BPA was evaluated and the pharmacokinetics of [ 18 F]FBPA investigated by compartment modeling., Results: We found a significant correlation between [ 18 F]FBPA and [ 10 B]L-BPA uptake in tumors and various organs as well as high accumulation levels in pancreas and kidneys as reported in previous studies. Tumor-to-liver ratios of [ 18 F]FBPA ranged from 1.2 to 1.5. Preloading did not increase the uptake of [ 18 F]FBPA or [ 10 B]L-BPA in any organ and compartment modeling showed no statistically significant differences in [ 18 F]FBPA tumor kinetics., Conclusions: [ 18 F]FBPA-PET predicts [ 10 B]L-BPA concentration after amino acid preloading in HuH-7 hepatocellular carcinoma models. Preloading had no effect on tumor uptake of [ 18 F]FBPA., Advances in Knowledge: Despite differences in chemical structure and administered dose [ 18 F]FBPA and [ 10 B]L-BPA demonstrate an equivalent biodistribution in a preclinical tumor model. IMPLICATIONS FOR PATIENT CARE: [ 18 F]FBPA-PET is suitable for treatment planning and dose calculations in BNCT applications for liver malignancies. However, alternative tracers with more favorable tumor-to-liver ratios should be investigated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Positron emission tomography (PET) using fluorine-18 ( 18 F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[ 18 F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[ 18 F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [ 18 F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [ 18 F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10). Both radiolabeling precursor β-6 and unlabeled reference compound β-1 were prepared in multistep syntheses starting from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. In vitro experiments demonstrated an interaction of β-1 with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of β-[ 18 F]1 in tumor cell lines. In biodistribution studies in healthy mice β-[ 18 F]1 showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13±0.22 (n=4) at 2h after administration of β-[ 18 F]1. In ex vivo autoradiography experiments β-[ 18 F]1 distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, β-[ 18 F]1 shows potential as PET hypoxia radiotracer which merits further investigation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)