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Increasing extracellular levels of serotonin (5-HT) in the brain ameliorates symptoms of depression and anxiety-related disorders, e.g. social phobias and post-traumatic stress disorder. Recent evidence from preclinical and clinical studies established the potential of drugs inducing the release of 5-HT via the 5-HT-transporter. Nevertheless, current 5-HT releasing compounds under clinical investigation carry the risk for abuse and deleterious side effects. Here, we demonstrate that S-enantiomers of certain ring-substituted cathinones show preference for the release of 5-HT ex vivo and in vivo, and exert 5-HT-associated effects in preclinical behavioral models. Importantly, the lead cathinone compounds (i) do not induce substantial dopamine release and (ii) display reduced off-target activity at vesicular monoamine transporter-2 and 5-HT2B-receptors; indicative of low abuse-liability and low potential for adverse events. Taken together, our findings identify these agents as first-in class leads that may prove useful for the treatment of disorders where elevation of 5-HT has proven beneficial.

Die manuelle Montage zählt durch mangelnde Schnittstellen zur automatisierten Datenerfassung häufig zu den blinden Flecken für Industrie 4.0 und den dadurch möglichen Potenzialen zur Produktivitätssteigerung. Echtzeitlokalisierung bietet hier nicht nur die Möglichkeit Verschwendung durch Laufwege zu analysieren, sondern lässt sich auch für geofencing-basierte Produktionssteuerung nutzen. Der hier beschriebene systematische Vergleich zeigt welche Technologie sich hierfür am besten eignet. Due to a lack of interfaces for automated data acquisition, manual assembly is often among the blind spots for Industry 4.0 and the hoped-for potential for increasing productivity. Here, real-time localization not only offers the possibility of analyzing waste caused by movement, but can also be used for geofencing-based production control. The systematic comparison described here shows which technology is best suited for this purpose.

Die Steigerung der Produktivität und die damit einhergehende kontinuierliche Optimierung von Produktionsprozessen sind für produzierende Unternehmen wesentliche Voraussetzungen zur Sicherung der Wettbewerbsfähigkeit in der Zukunft. Insbesondere in der manuellen Montage ist die aufwandsarme Erhebung der dafür erforderlichen Datenbasis jedoch eine große Herausforderung. Dieser Beitrag stellt ein modulares Sensorsystem zur automatisierten Datenerhebung und Analyse von manuellen Montageprozessen vor und zeigt dessen Potenziale anhand eines Industriebeispiels auf. Increasing productivity and the constant optimization of production processes is crucial for manufacturing companies to remain competitive in future. However, in manual assembly processes, data acquisition is still challenging. This article presents a modular sensor system for the automated data acquisition and analysis of manual assembly processes and shows its potential based on an industrial project.

Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also pro-duce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for deter-mining the in vivo profile of effects produced by psychostimulant drugs Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.

NT-pro-BNP is produced in the cardiac atria and ventricles in response to increased wall stress. It may be a marker of both AF disease progression and co-morbidities that affect success after pulmonary vein isolation (PVI). This single-center retrospective study analyzed the association between pre-procedural NT-pro-BNP serum levels and the long-term outcome after a first-ever PVI in cryo-technique. Patients were followed by searching the hospital information system and conducting structured telephone interviews. Treatment failure was defined as any relapse of atrial fibrillation (AF) occurring 90 days after the index PVI at the earliest. Kaplan–Meier survival curves and Cox proportional hazards models were computed to assess the impact of NT-pro-BNP on AF recurrence. Following 374 patients over a median of 3.8 years (range: 0.25–9.4 years), baseline NT-pro-BNP was associated with the combined endpoint in univariate analysis (HR 1.04 per 100 pg/mL increase, 95% CI: 1.02–1.07, p < 0.001). Results were virtually unchanged in the multivariate model or if the data were log-transformed. Intraprocedural left atrial pressure correlated positively with log NT-pro-BNP. NT-pro-BNP was associated with AF relapse during a long-term follow-up after first-ever cryo-PVI in our cohort of patients with predominantly normal left ventricular function. This lab parameter is easy to obtain and has significant potential to guide treatment decisions.

NT-pro-BNP is produced in the cardiac atria and ventricles in response to increased wall stress. It may be a marker of both AF disease progression and co-morbidities that affect success after pulmonary vein isolation (PVI). This single-center retrospective study analyzed the association between pre-procedural NT-pro-BNP serum levels and the long-term outcome after a first-ever PVI in cryo-technique. Patients were followed by searching the hospital information system and conducting structured telephone interviews. Treatment failure was defined as any relapse of atrial fibrillation (AF) occurring 90 days after the index PVI at the earliest. Kaplan-Meier survival curves and Cox proportional hazards models were computed to assess the impact of NT-pro-BNP on AF recurrence. Following 374 patients over a median of 3.8 years (range: 0.25-9.4 years), baseline NT-pro-BNP was associated with the combined endpoint in univariate analysis (HR 1.04 per 100 pg/mL increase, 95% CI: 1.02-1.07

Glioblastoma (GBM), the most malignant tumor of the central nervous system, is marked by its dynamic response to microenvironmental niches. In particular, this cellular plasticity contributes to the development of an immediate resistance during tumor treatment. Novel insights into the developmental trajectory exhibited by GBM show a strong capability to respond to its microenvironment by clonal selection of specific phenotypes. Using the same mechanisms, malignant GBM do develop intrinsic mechanisms to resist chemotherapeutic treatments. This resistance was reported to be sustained by the paracrine and autocrine glutamate signaling via ionotropic and metabotropic receptors. However, the extent to which glutamatergic signaling modulates the chemoresistance and transcriptional profile of the GBM remains unexplored. In this study we aimed to map the manifold effects of glutamate signaling in GBM as the basis to further discover the regulatory role and interactions of specific receptors, within the GBM microenvironment. Our work provides insights into glutamate release dynamics, representing its importance for GBM growth, viability, and migration. Based on newly published multi-omic datasets, we explored the and characterized the functions of different ionotropic and metabotropic glutamate receptors, of which the metabotropic receptor 3 (GRM3) is highlighted through its modulatory role in maintaining the ability of GBM cells to evade standard alkylating chemotherapeutics. We addressed the clinical relevance of GRM3 receptor expression in GBM and provide a proof of concept where we manipulate intrinsic mechanisms of chemoresistance, driving GBM towards chemo-sensitization through GRM3 receptor inhibition. Finally, we validated our findings in our novel human organotypic section-based tumor model, where GBM growth and proliferation was significantly reduced when GRM3 inhibition was combined with temozolomide application. Our findings present a new picture of how glutamate signaling via mGluR3 interacts with the phenotypical GBM transcriptional programs in light of recently published GBM cell-state discoveries.

OBJECTIVES We reviewed our institutional experience with intravenous thrombolysis (TL) as first-line therapy in patients with Medtronic/HeartWare HVAD left ventricular assist device pump thrombosis (PT). METHODS From March 2006 to November 2018, 30 Medtronic/HeartWare HVAD left ventricular assist device patients had 48 PT events. We analysed outcomes with intravenous Alteplase as a first-line therapy for PT. Pump exchange or urgent heart transplantation was only considered after the failure of TL or existing contraindications to TL. RESULTS TL was used as the first-line therapy in 44 PT events in 28 patients without a contraindication to TL. TL was successful in 61.4% of PT events. More than 1 cycle of TL was necessary in 55.6% of events. The combined success of TL and heart transplantation or device exchange was 81.8%. In 15.9% of events, PT was fatal. Causes of death were severe complications (9.1%) related to TL or discontinuation of therapy for multi-organ failure (6.8%). Intracranial bleeding and arterial thromboembolism were observed in 4.5% and 11.5% of the PT events after TL. CONCLUSIONS Intravenous TL as a first-line therapy for PT in Medtronic/HeartWare HVAD patients can be a reasonable treatment option and does not preclude subsequent heart transplantation or device exchange. However, thromboembolic and bleeding complications are common. The decision to perform TL or device exchange should, therefore, be made on an individual basis after balancing the risks and benefits of different treatment approaches.

IntroductionDespite the paucity of evidence verifying its efficacy and safety, traditional Chinese medicine (TCM) is expanding in popularity and political support. Decisions to include TCM diagnoses in the International Classification of Diseases 11th Revision (ICD-11) by the World Health Organization (WHO) and campaigns to integrate TCM into national healthcare systems have occurred whilst the public perception and usage of TCM, especially in Europe, remains undetermined. Accordingly, this study investigates the popularity, usage patterns, perception of scientific support for TCM, and its relationship to homeopathy.MethodsA cross-sectional survey was performed in Austria and data from 1382 participants were analysed. A Bayesian network model retrieved partial correlations indicating distinct associations between sociodemographic determinants, complementary and alternative medicine (CAM) usage patterns, readiness to vaccinate, and TCM related variables.ResultsTCM was broadly known by the Austrian population (89.9% of women, 90.6% of men), with 58.9% of women and 39.5% of men using TCM between 2016 and 2019. 66.4% of women and 49.7% of men agreed with TCM being supported by science. We found a strong positive relationship between the perceived scientific support for TCM and trust in TCM-certified medical doctors. Moreover, perceived scientific support for TCM was negatively correlated with the proclivity to get vaccinated. Additionally, our Bayesian network model yielded distinct associations between TCM-, homeopathy-, and vaccination-related variables.ConclusionTCM is widely known within the Austrian general population and actively used by a substantial proportion. However, a crucial disparity exists between the commonly held public perception that TCM is scientific and findings from evidence-based studies. As public opinion towards TCM, and the proclivity to use it, are promoted through institutionalisation and official acknowledgement, it would be critical to sustain and support the distribution of unbiased, science-driven information by governmental institutions and policymakers to encourage informed patient-driven decision-making.Strengths and limitations of this studyThis is the first study to comprehensively explore the usage patterns and sociodemographic associations of TCM in a European population, not based on data deriving from the seventh round of the European Social Survey.We are the first study on CAM usage patterns to graphically explore and report data using a Bayesian Gaussian copula graphical model—thereby, retrieving distinct partial correlations.We provide an up-to-date summary of TCM, set forth our findings at a geopolitical scale and highlight that the discrepancy between the paucity of evidence underpinning most TCM modalities and the international promotion of TCM is also reflected in the widely-held public perception that TCM is supported by science.Due to the retrospective character of our cross-sectional survey, answers are naturally prone to recall and response bias.Our sample is skewed towards the young, people with higher levels of education, and shows a relative underrepresentation of males. Therefore, we post-stratified our sample using representative data from Austria’s federal statistical office “Statistik Austria” as a robustness check.

Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.

Klassische Methoden der Montageplanung kommen im volatilen Umfeld oft an ihre Grenzen. Eine Methodik zur automatisierten Generierung einer Montageablaufplanung begegnet diesen Herausforderungen. Diese Methodik wurde in einem Projekt bei der Elabo GmbH zur Optimierung der Montage angewandt. Die Projektergebnisse werden in diesem Beitrag vorgestellt und kritisch reflektiert. In a volatile environment, classical methods of assembly planning often reach their limits. This paper describes a methodology for automatically planning an assembly sequence in order to meet these challenges. The methodology was applied to a project at Elabo GmbH to optimize assembly. The project results are presented and reflected critically in this publication.

α-Pyrrolidinovalerophenone (αPVP) is a psychostimulant and drug of abuse associated with severe intoxications in humans. αPVP exerts long-lasting psychostimulant effects, when compared to the classical dopamine transporter (DAT) inhibitor cocaine. Here, we compared the two enantiomeric forms of αPVP, the R- and the S-αPVP, with cocaine using a combination of in silico, in vitro and in vivo approaches. We found that αPVP enantiomers substantially differ from cocaine in their binding kinetics. The two enantiomers differ from each other in their association rates. However, they show similar slow dissociation rates leading to pseudo-irreversible binding kinetics at DAT. The pseudo-irreversible binding kinetics of αPVP is responsible for the observed non-competitive pharmacology and it correlates with persistent psychostimulant effects in mice. Thus, the slow binding kinetics of αPVP enantiomers profoundly differ from the fast kinetics of cocaine both in vitro and in vivo, suggesting drug-binding kinetics as a potential driver of psychostimulant effects in vivo.

Organic cation transporters 1-3 (OCT1-3, SLC22A1-3) and the plasma membrane monoamine transporter (PMAT, SLC29A4) play a major role in maintaining monoaminergic equilibrium in the central nervous system. With many psychoactive substances interacting with OCT1-3 and PMAT, a growing literature focuses on characterizing their properties via in vitro and in vivo studies. In vitro studies mainly aim at characterizing compounds as inhibitors or substrates of murine, rat, and human isoforms. The preponderance of studies has put emphasis on phenylalkylamine derivatives, but ketamine and opioids have also been investigated. Studies employing in vivo (knockout) models mostly concentrate on the interaction of psychoactive substances and OCT3, with an emphasis on stress and addiction, pharmacokinetics, and sensitization to psychoactive drugs. The results highlight the importance of OCT3 in the mechanism of action of psychoactive compounds. Concerning in vivo studies, a veritable research gap concerning OCT1, 2, and PMAT exists. This review provides an overview and summary of research conducted in this field of research.

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC

Successful emotion regulation plays a key role in psychological health and well-being. This study examines (1) whether cognitive control and corresponding neural connectivity are associated with emotion regulation and (2) to what extent external instructions can improve emotion regulation in individuals with low vs. high cognitive control capacity. For this, emotion regulation capabilities and the impact of emotion regulation on a subsequent emotional Stroop task was tested in participants with low (N = 25) vs. high impulsivity (N = 32). The classification according to impulsivity is based upon the stable correlation between high impulsivity and reduced cognitive control capacity. A negative emotion inducing movie scene was presented with the instruction to either suppress or allow all emotions that arose. This was followed by an emotional Stroop task. Electromyography (EMG) over the corrugator supercilii was used to assess the effects of emotion regulation. Neurophysiological mechanisms were measured using functional near-infrared spectroscopy over frontal brain areas. While EMG activation was low in the low-impulsive group independent of instruction, high-impulsive participants showed increased EMG activity when they were not explicitly instructed to suppress arising emotions. Given the same extent of functional connectivity within frontal lobe networks, the low-impulsive participants controlled their emotions better (less EMG activation) than the high-impulsive participants. In the Stroop task, the low-impulsive subjects performed significantly better. The emotion regulation condition had no significant effect on the results. We conclude that the cognitive control network is closely associated with emotion regulation capabilities. Individuals with high cognitive control show implicit capabilities for emotion regulation. Individuals with low cognitive control require external instructions (= explicit emotion regulation) to achieve similarly low expressions of emotionality. Implications for clinical applications aiming to improve emotion regulation are discussed.

Organic cation transporters 1-3 (OCT1-3, SLC22A1-3) and the plasma membrane monoamine transporter (PMAT, SLC29A4) play a major role in maintaining monoaminergic equilibrium in the central nervous system. With many psychoactive substances interacting with OCT1-3 and PMAT, a growing literature focuses on characterizing their properties via in vitro and in vivo studies. In vitro studies mainly aim at characterizing compounds as inhibitors or substrates of murine, rat, and human isoforms. The preponderance of studies has put emphasis on phenylalkylamine derivatives, but ketamine and opioids have also been investigated. Studies employing in vivo (knockout) models mostly concentrate on the interaction of psychoactive substances and OCT3, with an emphasis on stress and addiction, pharmacokinetics, and sensitization to psychoactive drugs. The results highlight the importance of OCT3 in the mechanism of action of psychoactive compounds. Concerning in vivo studies, a veritable research gap concerning OCT1, 2, and PMAT exists. This review provides an overview and summary of research conducted in this field of research.

Patients with symptomatic, drug-refractory atrial fibrillation (AF) are frequently treated with catheter ablation. Cryo-ablation has been established as an alternative to radiofrequency ablation but long-term outcome data are still limited. This study aimed at elucidating the influence of the left atrial volume index (LAVI), derived from cardiac computed tomography (cCT) data, on the long-term outcome of ablation-naive AF patients, after their first cryo-ablation. 415 patients (n = 290 [69.90%] male, 60.00 [IQR: 53.00 to 68.00] years old) who underwent a cCT and subsequent cryo-ablation index procedure were included in this single centre retrospective data analysis. A composite end point was defined (AF on electrocardiogram and/or electric cardioversion and/or re-do). Patients were closely followed for a year and then contacted for long-term follow-up after a median of 53.00 months (IQR: 34.50 to 73.00). Statistical analyses of the outcome and predictors of AF recurrence were conducted. In 224 patients (53.98%) no evidence of AF recurrence could be found. LAVI differed significantly between the positive and adverse (AF recurrence) outcome group (49.96 vs 56.07 ml/m2, p

Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.

Real-time inference of human motor volition has great potential for the intuitive control of robotic devices. Toward this end, myoelectric pattern recognition (MPR) has shown promise in the control of prosthetic limbs. Interfering noise and susceptibility to motion artifacts have hindered the use of MPR outside controlled environments, and thus represent an obstacle for clinical use. Advanced signal processing techniques have been previously proposed to improve the robustness of MPR systems. However, the investigation of such techniques have been limited to offline implementations with long time windows, which makes real-time use unattainable. In this work, we present a novel algorithm using discrete and stationary wavelet transforms for MPR that can be executed in real-time. Our wavelet-based de-noising algorithm outperformed conventional band-pass filtering (up to 100 Hz) and improved real-time MPR in the presence of motion artifacts, as measured by the motion test. Improved signal-to-noise ratio was found not to be crucial in offline MPR, as machine learning algorithms can integrate high but consistent noise as part of the signal. However, varying interference is expected to occur in real life where signal processing algorithms, as the one introduced in this paper, would potentially have a positive impact. Furthermore implementation of these algorithms in a prosthetic embedded system is required to validate their feasibility and usability during activities of the daily living.