Publications by authors named "Jan Richter"

95 Publications

Umsetzbarkeit und Erleben: Erste Erfahrungen mit einer Kurzform der anwendungsorientierten Parcoursprüfung im MSc-Studiengang Psychologie.

Verhaltenstherapie 2020 Jun 12;30(2):141-155. Epub 2020 Jun 12.

Universität Greifswald, Greifswald, Deutschland.

Einleitung: Voraussetzung für die Approbation im Rahmen der neuen Psychotherapeutenausbildung ist u.a. das Bestehen einer anwendungsorientierten Parcoursprüfung. Da diese Prüfung von Lehrenden und Studierenden als Herausforderung angesehen wird, wurde eine Kurzform der Parcoursprüfung im Rahmen einer Modulprüfung des MSc-Studiengangs Psychologie eingeführt und evaluiert.

Methode: Für die 15-minütige Parcoursprüfung wurden 9 Kompe-tenzbereiche basierend auf praxisorientierten Psychotherapieseminaren entwickelt, von denen 2 jeweils geprüft wurden. Zur Standardisierung der Benotung wurde ein Bewertungsbogen konzipiert. Eine Mitarbeiterin erhielt ein Training als Simulationspatientin. Für die Evaluation wurde ein Fragebogen entwickelt, welcher u.a. die Umsetzbarkeit und das subjektive Erleben dieses Prüfungsformats aus der Sicht der an der Prüfung beteiligten Personen erfasst.

Ergebnisse: 14 Prüfungskandidierende ließen sich durch 3 Prüfende prüfen. Die Gesamtdurchschnittsnote betrug 1,19 (Bereich: 1,0-2,3). Die Auswertung der Fragebögen zeigte, dass alle drei Gruppen die Prüfung als geeignet, die praktischen Fertigkeiten abzubilden, objektiv und praxisnah empfanden. Von den Prüfungskandidierenden gaben 50% an, dass die Prüfung sie gestresst habe, während die Simulationspatientin sich nie und die Prüfenden sich gar nicht (78%) oder kaum (22%) gestresst fühlten.

Diskussion: Die Ergebnisse dieser Pilotstudie weisen auf eine gute Umsetzbarkeit der Parcoursprüfung hin, wenngleich sie auch mit Stress für die Prüfungskandidierenden verbunden war. Die Pilotstudie wird limitiert durch eine kleine und wahrscheinlich verzerrte Stichprobe (motivierte Studierende) ohne Vergleichsgruppe. Abschließend werden die Vor- und Nachteile dieses Prüfungsmodells kritisch diskutiert.
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http://dx.doi.org/10.1159/000507820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360497PMC
June 2020

Efficacy of temporally intensified exposure for anxiety disorders: A multicenter randomized clinical trial.

Depress Anxiety 2021 Jul 22. Epub 2021 Jul 22.

Institute of Clinical Psychology & Psychotherapy, Technische Universität Dresden, Dresden, Germany.

Background: The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions.

Methods: This multicenter randomized controlled trial compared two variants of prediction error-based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx-I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx-S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6-months follow-up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression.

Results: Both treatments resulted in substantial improvements at post (PeEx-I: d  = 1.50, PeEx-S: d  = 1.78) and follow-up (PeEx-I: d  = 2.34; PeEx-S: d  = 2.03). Both groups showed formally equivalent symptom reduction at post and follow-up. However, time until response during treatment was 32% shorter in PeEx-I (median = 68 days) than PeEx-S (108 days; TR  = 0.68). Interestingly, drop-out rates were lower during intensified exposure. PeEx-I was also superior in reducing disability days and improving quality of life at follow-up without increasing relapse.

Conclusions: Both treatment variants focusing on the transdiagnostic exposure-based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop-out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.
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http://dx.doi.org/10.1002/da.23204DOI Listing
July 2021

Molecular epidemiology of SARS-CoV-2 in Cyprus.

PLoS One 2021 21;16(7):e0248792. Epub 2021 Jul 21.

Molecular Virology Department, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Whole genome sequencing of viral specimens following molecular diagnosis is a powerful analytical tool of molecular epidemiology that can critically assist in resolving chains of transmission, identifying of new variants or assessing pathogen evolution and allows a real-time view into the dynamics of a pandemic. In Cyprus, the first two cases of COVID-19 were identified on March 9, 2020 and since then 33,567 confirmed cases and 230 deaths were documented. In this study, viral whole genome sequencing was performed on 133 SARS-CoV-2 positive samples collected between March 2020 and January 2021. Phylogenetic analysis was conducted to evaluate the genomic diversity of circulating SARS-CoV-2 lineages in Cyprus. 15 different lineages were identified that clustered into three groups associated with the spring, summer and autumn/winter wave of SARS-CoV-2 incidence in Cyprus, respectively. The majority of the Cypriot samples belonged to the B.1.258 lineage first detected in September that spread rapidly and largely dominated the autumn/winter wave with a peak prevalence of 86% during the months of November and December. The B.1.1.7 UK variant (VOC-202012/01) was identified for the first time at the end of December and spread rapidly reaching 37% prevalence within one month. Overall, we describe the changing pattern of circulating SARS-CoV-2 lineages in Cyprus since the beginning of the pandemic until the end of January 2021. These findings highlight the role of importation of new variants through travel towards the emergence of successive waves of incidence in Cyprus and demonstrate the importance of genomic surveillance in determining viral genetic diversity and the timely identification of new variants for guiding public health intervention measures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248792PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294526PMC
July 2021

Transfer of exposure therapy effects to a threat context not considered during treatment in patients with panic disorder and agoraphobia: Implications for potential mechanisms of change.

Behav Res Ther 2021 07 12;142:103886. Epub 2021 May 12.

Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany.

Further developments of exposure-based therapy (EBT) require more knowledge about transfer of treatment to non-trained everyday contexts. However, little is known about transfer effects of EBT. Using a standardized EBT protocol in 275 patients with panic disorder and agoraphobia we investigated the transfer of EBT to a highly standardized context during a Behavioral Avoidance Test (BAT; being entrapped in a small and dark test chamber) and not part of the exposure sessions. Patients of a treatment group underwent the BATs before treatment (t1), after a preparatory treatment phase (t2), and after an agoraphobic exposure phase (t3) and were compared with wait-list control patients, who repeated BAT assessments across the same time period. We found stronger reductions in avoidance behavior, reported fear, and autonomic arousal during the BAT from t1 to t3 in the treatment group patients who were anxious during t1 relative to the anxious but untreated patients. Fear reduction was related to treatment outcome indicating the contribution of transfer effects to successful EBT. Interestingly, reduction varied for different fear response systems suggesting different processes to may be involved in transfer effects. Importantly, final BAT assessment still evoked residual fear in the treatment group as compared to BAT non-anxious control patients, suggesting limited transfer effects - one possible reason for the return of symptoms in new situations.
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http://dx.doi.org/10.1016/j.brat.2021.103886DOI Listing
July 2021

Neural adaptation of cingulate and insular activity during delayed fear extinction: A replicable pattern across assessment sites and repeated measurements.

Neuroimage 2021 08 19;237:118157. Epub 2021 May 19.

Department of Psychiatry and Psychotherapy and Center for Mind, Brain and Behavior - CMBB, Philipps-Universität Marburg, Germany.

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24 h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118157DOI Listing
August 2021

Association of Epstein-Barr virus latently expressed genes with multiple sclerosis.

Mult Scler Relat Disord 2021 Jul 7;52:103008. Epub 2021 May 7.

Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 2371; Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 2371.

Background: Despite mounting evidence supporting an etiologic role for Epstein-Barr virus (EBV) in multiple sclerosis (MS), the exact mechanisms through which the virus may contribute to disease development are still unknown. The aim of this study was to analyze seven highly polymorphic EBV latently expressed genes in individuals diagnosed with MS in comparison to healthy controls (HC), to investigate the possible association of EBV variants with an individual's risk towards MS.

Methods: B-lymphocytes were isolated from MS patients (n = 30) and HC (n = 33) for the isolation of EBV genomic DNA. Sanger sequencing was employed to analyze EBV latent gene regions.

Results: A total of 26 variants were detected in our cohort, 17 of which were significantly associated with the MS group while nine were significantly associated with HC. Following the designation of EBV alleles based on these variants, MS risk was found to be significantly associated with the presence of the EBNA3B2.1 allele (p = 0.0008) and LMP1.1 allele (p = 0.01), whereas the EBNA1.3 allele (p = 0.005), EBNA2.1 allele (p = 0.001) as well as the EBNA3B2.2 allele (p = 0.0003) appeared to provide a protective role.

Conclusions: This study indicates a marked association between EBV genetic variants and MS, lending further support towards possible molecular mechanisms through which EBV may contribute to disease development.
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http://dx.doi.org/10.1016/j.msard.2021.103008DOI Listing
July 2021

Reprogramming Intestinal Epithelial Cell Polarity by Interleukin-22.

Front Med (Lausanne) 2021 12;8:656047. Epub 2021 Apr 12.

Department for Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Interleukin-22 (IL-22) impacts the integrity of intestinal epithelia and has been associated with the development of colitis-associated cancer and inflammatory bowel diseases (IBD). Previous data suggest that IL-22 protects the mucosal barrier and promotes wound healing and barrier defect. We hypothesized, that IL-22 modulates cell polarity of intestinal epithelial cells (IECs) acting on tight junction assembly. The aim of the study was to investigate IL-22-dependent mechanisms in the reprogramming of intestinal epithelia. IECs were exposed to IL-22 at various concentrations. IECs in Matrigel® were grown to 3-dimensional cysts in the presence or absence of IL-22 and morphology and expression of polarity proteins were analyzed by confocal microscopy. Epithelial cell barrier (TER and sandwich assay) and TJ assembly analysis (calcium-switch assay) were performed. TJ and cell polarity protein expression were assessed by western blotting and confocal microscopy. Cell migration and invasion assays were performed. Induction of epithelial-mesenchymal transition (EMT) was assessed by RT-qPCR analysis and western blotting. Signaling pathway analyses were performed by phosphoblotting and functional assays after blocking STAT3 and ERK signaling pathways. Using the toxoplasma-model of terminal ileitis, IL-22-knock-out mice were compared to wild-type littermates, analyzed for barrier function using one-path-impedance-analysis and macromolecular flux (H3-mannitol, Ussing-chambers). IECs exhibited a barrier defect after IL-22 exposure. TJ protein distribution and expression were severely impaired. Delayed recovery in the calcium-switch assay was observed suggesting a defect in TJ assembly. Analyzing the 3D-cyst model, IL-22 induced multi-lumen and aberrant cysts, and altered the localization of cell polarity proteins. Cell migration and invasion was caused by IL-22 as well as induction of EMT. Interestingly, only inhibition of the MAPK pathway, rescued the TJal barrier defect, while blocking STAT3 was relevant for cell survival. In addition, ileal mucosa of IL-22 deficient mice was protected from the barrier defect seen in Toxoplasma gondii-induced ileitis in wild type mice shown by significantly higher Re values and correspondingly lower macromolecule fluxes. IL-22 impairs intestinal epithelial cell barrier by inducing EMT, causing defects in epithelial cell polarity and increasing cell motility and cell invasion. IL-22 modulates TJ protein expression and mediates tight junctional (TJal) barrier defects via ERK pathway.
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http://dx.doi.org/10.3389/fmed.2021.656047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072225PMC
April 2021

Vagal control of the heart decreases during increasing imminence of interoceptive threat in patients with panic disorder and agoraphobia.

Sci Rep 2021 Apr 12;11(1):7960. Epub 2021 Apr 12.

Department of Biological and Clinical Psychology, University of Greifswald, Franz-Mehring-Str. 47, 17487, Greifswald, Germany.

Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034.
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http://dx.doi.org/10.1038/s41598-021-86867-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041829PMC
April 2021

Attentive immobility in the face of inevitable distal threat-Startle potentiation and fear bradycardia as an index of emotion and attention.

Psychophysiology 2021 06 24;58(6):e13812. Epub 2021 Mar 24.

Department of Physiological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany.

During fear conditioning, a cue (CS) signals an inevitable distal threat (US) and evokes a conditioned response that can be described as attentive immobility (freezing). The organism remains motionless and monitors the source of danger while startle responses are potentiated, indicating a state of defensive hypervigilance. Although in animals vagally mediated fear bradycardia is also reliably observed under such circumstances, results are mixed in human fear conditioning. Using a single-cue fear conditioning and extinction protocol, we tested cardiac reactivity and startle potentiation indexing low-level defensive strategies in a fear-conditioned (n = 40; paired presentations of CS and US) compared with a non-conditioned control group (n = 40; unpaired presentations of CS and US). Additionally, we assessed shock expectancy ratings on a trial-by-trial basis indexing declarative knowledge of the previous contingencies. Half of each group underwent extinction under sham or active transcutaneous vagus nerve stimulation (tVNS), serving as additional proof of concept. We found stronger cardiac deceleration during CS presentation in the fear learning relative to the control group. This learned fear bradycardia was positively correlated with conditioned startle potentiation but not with declarative knowledge of CS-US contingencies. TVNS abolished differences in heart rate changes between both groups and removed the significant correlation between late cardiac deceleration and startle potentiation in the fear learning group. Results suggest, fear-conditioned cues evoke attentive immobility in humans, characterized by cardiac deceleration and startle potentiation. Such defensive response pattern is elicited by cues predicting inevitable distal threat and resembles conditioned fear responses observed in rodents.
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http://dx.doi.org/10.1111/psyp.13812DOI Listing
June 2021

AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy.

Gene Ther 2021 Mar 10. Epub 2021 Mar 10.

Neuroscience Department, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus.

Mutations in the GJB1 gene, encoding the gap junction (GJ) protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We developed a gene therapy approach for CMT1X using an AAV9 vector to deliver the GJB1/Cx32 gene under the myelin protein zero (Mpz) promoter for targeted expression in Schwann cells. Lumbar intrathecal injection of the AAV9-Mpz.GJB1 resulted in widespread biodistribution in the peripheral nervous system including lumbar roots, sciatic and femoral nerves, as well as in Cx32 expression in the paranodal non-compact myelin areas of myelinated fibers. A pre-, as well as post-onset treatment trial in Gjb1-null mice, demonstrated improved motor performance and sciatic nerve conduction velocities along with improved myelination and reduced inflammation in peripheral nerve tissues. Blood biomarker levels were also significantly ameliorated in treated mice. This study provides evidence that a clinically translatable AAV9-mediated gene therapy approach targeting Schwann cells could potentially treat CMT1X.
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http://dx.doi.org/10.1038/s41434-021-00250-0DOI Listing
March 2021

Latent class growth analyses reveal overrepresentation of dysfunctional fear conditioning trajectories in patients with anxiety-related disorders compared to controls.

J Anxiety Disord 2021 03 18;78:102361. Epub 2021 Jan 18.

Department of Clinical Psychology, Utrecht University, Utrecht, The Netherlands; Altrecht Academic Anxiety Center, Utrecht, The Netherlands; Department of Psychiatry, University Medical Center Groningen and University of Groningen, GGZ Drenthe, Department of Specialist Training, The Netherlands. Electronic address:

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety-related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (≥50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.
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http://dx.doi.org/10.1016/j.janxdis.2021.102361DOI Listing
March 2021

Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis.

Eur Neuropsychopharmacol 2021 Mar 20;44:105-120. Epub 2021 Jan 20.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany; Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.
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http://dx.doi.org/10.1016/j.euroneuro.2021.01.004DOI Listing
March 2021

The modulating impact of cigarette smoking on brain structure in panic disorder: a voxel-based morphometry study.

Soc Cogn Affect Neurosci 2020 10;15(8):849-859

Department of Psychology, Humboldt-Universität zu Berlin, Berlin 10117, Germany.

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. In total, 143 PD patients (71 smokers) and 178 healthy controls (62 smokers) participated in a multicenter magnetic resonance imaging (MRI) study. T1-weighted images were used to examine brain structural alterations using voxel-based morphometry in a priori defined regions of the defensive system network. PD was associated with gray matter volume reductions in the amygdala and hippocampus. This difference was driven by non-smokers and absent in smoking subjects. Bilateral amygdala volumes were reduced with increasing health burden (neither PD nor smoking > either PD or smoking > both PD and smoking). As smoking can narrow or diminish commonly observed structural abnormalities in PD, the effect of smoking should be considered in MRI studies focusing on patients with pathological forms of fear and anxiety. Future studies are needed to determine if smoking may increase the risk for subsequent psychopathology via brain functional or structural alterations.
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http://dx.doi.org/10.1093/scan/nsaa103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543937PMC
October 2020

Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures.

Transl Psychiatry 2020 04 21;10(1):110. Epub 2020 Apr 21.

Department of Biological and Clinical Psychology/Psychotherapy, University of Greifswald, Greifswald, Germany.

Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients' pretreatment extinction learning performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment procedures. Therefore, we developed an extinction-training protocol highly tailored to the procedure of exposure therapy and tested it in two samples of 46 subjects in total. By using instructed fear acquisition training, including a consolidation period overnight, we wanted to ensure that the conditioned fear response was well established prior to extinction training, which is the case in patients with anxiety disorders prior to treatment. Moreover, the extinction learning process was analyzed on multiple response levels, comprising unconditioned stimulus (US) expectancy ratings, autonomic responses, defensive brain stem reflexes, and neural activation using functional magnetic resonance imaging. Using this protocol, we found robust fear conditioning and slow-speed extinction learning. We also observed within-group heterogeneity in extinction learning, albeit a stable fear response at the beginning of the extinction training. Finally, we found discordance between different response systems, suggesting that multiple processes are involved in extinction learning. The paradigm presented here might help to ameliorate the association between extinction learning performance assessed in the laboratory and therapy outcomes and thus facilitate translational science in anxiety disorders.
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http://dx.doi.org/10.1038/s41398-020-0786-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174283PMC
April 2020

Promoting long-term inhibition of human fear responses by non-invasive transcutaneous vagus nerve stimulation during extinction training.

Sci Rep 2020 01 30;10(1):1529. Epub 2020 Jan 30.

University of Greifswald, Department of Physiological and Clinical Psychology/Psychotherapy, Franz-Mehring-Strasse 47, 17487, Greifswald, Germany.

Inhibiting fear-related thoughts and defensive behaviors when they are no longer appropriate to the situation is a prerequisite for flexible and adaptive responding to changing environments. Such inhibition of defensive systems is mediated by ventromedial prefrontal cortex (vmPFC), limbic basolateral amygdala (BLA), and brain stem locus-coeruleus noradrenergic system (LC-NAs). Non-invasive, transcutaneous vagus nerve stimulation (tVNS) has shown to activate this circuit. Using a multiple-day single-cue fear conditioning and extinction paradigm, we investigated long-term effects of tVNS on inhibition of low-level amygdala modulated fear potentiated startle and cognitive risk assessments. We found that administration of tVNS during extinction training facilitated inhibition of fear potentiated startle responses and cognitive risk assessments, resulting in facilitated formation, consolidation and long-term recall of extinction memory, and prevention of the return of fear. These findings might indicate new ways to increase the efficacy of exposure-based treatments of anxiety disorders.
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http://dx.doi.org/10.1038/s41598-020-58412-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992620PMC
January 2020

Simple Syntheses of New Pegylated Trehalose Derivatives as a Chemical Tool for Potential Evaluation of Cryoprotectant Effects on Cell Membrane.

Molecules 2020 Jan 23;25(3). Epub 2020 Jan 23.

Institute of Physics, Czech Academy of Sciences, Na Slovance 1999/2, 182 21 Praha 8, Czech Republic.

In our work, we developed the synthesis of new polyfunctional pegylated trehalose derivatives and evaluated their cryoprotective effect using flow cytometry. We showed that new compounds (modified trehaloses) bound to appropriate extracellular polymeric cryoprotectants could be helpful as a chemical tool for the evaluation of their potential toxic cell membrane influences. Our aim was to form a chemical tool for the evaluation of cryoprotectant cell membrane influences, which are still not easily predicted during the freezing/thawing process. We combined two basic cryoprotectants: polyethyleneglycols (PEGs) and trehalose in the new chemical compounds-pegylated trehalose hybrids. If PEG and trehalose are chemically bound and trehalose is adsorbed on the cell surface PEGs molecules which are, due to the chemical bonding with trehalose, close to the cell surface, can remove the cell surface hydration layer which destabilizes the cell membrane. This was confirmed by the comparison of new material, PEG, trehalose, and their mixture cryoprotective capabilities.
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http://dx.doi.org/10.3390/molecules25030497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038055PMC
January 2020

Navigating the garden of forking paths for data exclusions in fear conditioning research.

Elife 2019 12 16;8. Epub 2019 Dec 16.

Institute of Cognitive Neuroscience, Department of Cognitive Psychology, Ruhr University Bochum, Bochum, Germany.

In this report, we illustrate the considerable impact of researcher degrees of freedom with respect to exclusion of participants in paradigms with a learning element. We illustrate this empirically through case examples from human fear conditioning research, in which the exclusion of 'non-learners' and 'non-responders' is common - despite a lack of consensus on how to define these groups. We illustrate the substantial heterogeneity in exclusion criteria identified in a systematic literature search and highlight the potential problems and pitfalls of different definitions through case examples based on re-analyses of existing data sets. On the basis of these studies, we propose a consensus on evidence-based rather than idiosyncratic criteria, including clear guidelines on reporting details. Taken together, we illustrate how flexibility in data collection and analysis can be avoided, which will benefit the robustness and replicability of research findings and can be expected to be applicable to other fields of research that involve a learning element.
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http://dx.doi.org/10.7554/eLife.52465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989118PMC
December 2019

Effect of CBT on Biased Semantic Network in Panic Disorder: A Multicenter fMRI Study Using Semantic Priming.

Am J Psychiatry 2020 03 16;177(3):254-264. Epub 2019 Dec 16.

Department of Psychiatry and Psychotherapy and Marburg Center for Mind, Brain, and Behavior, Philipps-University Marburg, Marburg, Germany (Yang, Konrad, Straube, Kircher); Department of Psychiatry, Psychosomatics, and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, University of Würzburg, Würzburg, Germany (Lueken, Herrmann, Deckert); Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany (Lueken); Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany (Richter, Hamm); Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany (Wittmann, Ströhle); Department of Psychiatry, Agaplesion Diakonieklinikum Rotenburg (Wümme), Germany (Konrad); Department of Clinical Radiology, University of Münster, Münster, Germany (Pfleiderer); Christoph-Dornier-Foundation for Clinical Psychology, Bremen, Germany (Lang); Department of Psychiatry and Psychotherapy, University of Hamburg, Hamburg, Germany (Lang); Functional Imaging Unit, Institute for Diagnostic Radiology and Neuroradiology, University of Greifswald, Greifswald, Germany (Lotze); Department of Psychiatry, University of Münster, Münster, Germany (Arolt); and Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany (Wittchen).

Objective: Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder.

Methods: An automatic semantic priming paradigm specifically tailored for panic disorder, in which panic symptoms (e.g., "dizziness") were primed by panic triggers (e.g., "elevator") compared with neutral words (e.g., "bottle"), was performed during functional MRI scanning with 118 patients with panic disorder (compared with 150 healthy control subjects) before and 42 patients (compared with 52 healthy control subjects) after an exposure-based CBT. Neural correlates were investigated by comparing 103 pairs of matched patients and control subjects at the baseline (for patients) or T1 (for control subjects) assessment and 39 pairs at the posttreatment or T2 assessment.

Results: At baseline or T1, patients rated panic-trigger/panic-symptom word pairs with higher relatedness and higher negative valence compared with healthy control subjects. Patients made faster lexical decisions to the panic-symptom words when they were preceded by panic-trigger words. This panic-priming effect in patients (compared with control subjects) was reflected in suppressed neural activation in the left and right temporal cortices and insulae and enhanced activation in the posterior and anterior cingulate cortices. After CBT, significant clinical improvements in the patient group were observed along with a reduction in relatedness and negative valence rating and attenuation of neural activation in the anterior cingulate cortex for processing of panic-trigger/panic-symptom word pairs.

Conclusions: The findings support a biased semantic network in panic disorder, which is normalized after CBT. Attenuation of anterior cingulate cortex activation for processing of panic-related associations provides a potential mechanism for future therapeutic interventions.
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http://dx.doi.org/10.1176/appi.ajp.2019.19020202DOI Listing
March 2020

Making translation work: Harmonizing cross-species methodology in the behavioural neuroscience of Pavlovian fear conditioning.

Neurosci Biobehav Rev 2019 12 12;107:329-345. Epub 2019 Sep 12.

Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.
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http://dx.doi.org/10.1016/j.neubiorev.2019.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822629PMC
December 2019

Association of rs7688285 allelic variation coding for GLRB with fear reactivity and exposure-based therapy in patients with panic disorder and agoraphobia.

Eur Neuropsychopharmacol 2019 10 20;29(10):1138-1151. Epub 2019 Aug 20.

Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Germany.

The gene coding for glycine receptor β subunits (GLRB) has been found to be related to panic disorder and agoraphobia (PD/AG) and to be associated with altered insular BOLD activation during fear conditioning, as an intermediate phenotype of defensive system reactivity in healthy subjects. In a multicenter clinical trial on PD/AG patients we investigated in three sub-samples whether GLRB allelic variation (A/G; A-allele identified as «risk») in the single nucleotide polymorphism rs7688285 was associated with autonomic (behavioral avoidance test BAT; n = 267 patients) and neural (differential fear conditioning; n = 49 patients, n = 38 controls) measures, and furthermore with responding towards exposure-based cognitive behavioral therapy (CBT, n = 184 patients). An interaction of genotype with current PD/AG diagnosis (PD/AG vs. controls; fMRI data only) and their modification after CBT was tested as well. Exploratory fMRI results prior to CBT, revealed A-allele carriers irrespective of diagnostic status to show overall higher BOLD activation in the hippocampus, motor cortex (MC) and insula. Differential activation in the MC, anterior cingulate cortex (ACC) and insula was found in the interaction genotype X diagnosis. Differential activation in ACC and hippocampus was present in differential fear learning. ACC activation was modified after treatment, while no overall rs7688285 dependent effect on clinical outcomes was found. On the behavioral level, A-allele carriers showed pronounced fear reactivity prior to CBT which partially normalized afterwards. In sum, rs7688285 variation interacts in a complex manner with PD/AG on a functional systems level and might be involved in the development of PD/AG but not in their treatment.
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http://dx.doi.org/10.1016/j.euroneuro.2019.07.133DOI Listing
October 2019

Molecular epidemiology of enteroviruses in Cyprus 2008-2017.

PLoS One 2019 8;14(8):e0220938. Epub 2019 Aug 8.

Department of Molecular Virology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Enteroviruses (EVs) are associated with a broad spectrum of disease manifestations, including aseptic meningitis, encephalitis, hand, foot and mouth disease, acute flaccid paralysis and acute flaccid myelitis with outbreaks being reported frequently world-wide. The aim of this study was the molecular characterization of all enteroviruses detected in Cyprus in the ten-year period from January 2008 and December 2017 as well as a description of the circulation patterns associated with the most frequently encountered genotypes. For this purpose, serum, cerebrospinal fluid, nasal swab, skin swab and/or stool samples from 2666 patients with a suspected EV infection were analysed between January 2008 and December 2017. Enteroviruses were detected in 295 (11.1%) patients, which were then investigated further for epidemiological analysis by VP1 genotyping. Overall, 24 different enterovirus types belonging to three different species were identified. The predominant species was EV-B (209/295, 71%), followed by species EV-A (77/295, 26.1%). Only one virus belonged to species EV-D, whereas EV-C enteroviruses were not identified at all. The most frequent genotypes identified were echovirus 30 (26.1%), echovirus 6 (14.2%) and coxsackievirus A6 (10.9%). While Echovirus 30 and echovirus 6 frequency was significantly higher in patients older than 3 years of age, the opposite was observed for CV-A16 and EV-A71, which dominated in young children less than 3 years. Importantly, for the current study period a significant increase of previously only sporadically observed EV-A types, such as EV-A71 and CV-A16 was noted. A phylogenetic analysis of EV-A71 showed that the majority of the EV-A71 strains from Cyprus belonged to sub-genogroup C1 and C2, with the exception of one C4 strain that was observed in 2011. The data presented provide a comprehensive picture of enteroviruses circulating in Cyprus over the last decade and will be helpful to clinicians and researchers involved in the treatment, prevention and control of enteroviral infections by helping interpret trends in enteroviral diseases by associating them with circulating serotypes, for studying the association of enteroviruses with clinical manifestations and develop strategies for designing future EV vaccines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220938PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687182PMC
March 2020

The Prevalence of Antibodies against Sandfly Fever Viruses and West Nile Virus in Cyprus.

J Arthropod Borne Dis 2019 Mar 30;13(1):116-125. Epub 2019 Mar 30.

Department of Molecular Virology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Background: Sandfly fever is an incapacitating disease caused by sandfly-borne Phleboviruses that can lead to meningitis, encephalitis or meningoencephalitis. West Nile virus (WNV), a mosquito-borne Flavivirus, can induce neuroinvasive disease manifested by meningitis, encephalitis or acute flaccid paralysis. Both vectors are endemic in Cyprus and very active during summer. The aims of this study were to determine first the prevalence of sandfly fever viruses (SFV) and WNV infections in Cyprus and second, to investigate their role in central nervous system (CNS) infections.

Methods: For the prevalence study, 327 sera collected in 2013 and 2014 were tested for anti-SFV and anti-WNV IgG using indirect immunofluorescence assay and ELISA, respectively. In order to investigate a possible role of SFV and WNV in CNS infections, 127 sera of patients presenting symptoms of SFV or WNV infections were screened for IgM specific to SFV and WNV.

Results: The overall anti-SFV IgG seroprevalence was 28% and was increasing with age (P< 0.01). The seroprevalence rate for anti-WNV IgG in Cyprus was 5%. Concerning the role of SFVs in CNS infections, anti-SFV IgM was detected in 8 out of 127 sera from selected patients presenting relevant symptoms of infections during vector's active period. In addition, anti-WNV IgM were detected in 17 out of the 127 patients with compatible symptoms.

Conclusion: The findings confirm the presence of sandfly fever and WNV in Cyprus and should, therefore, be considered in the differential diagnosis of patients with febrile illness/meningitis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643013PMC
March 2019

Occludin knockdown is not sufficient to induce transepithelial macromolecule passage.

Tissue Barriers 2019 4;7(2):1612661. Epub 2019 Jun 4.

e Institute of Biochemistry II , Jena University Hospital , Jena , Germany.

Occludin, a tight junction protein, has been reported to regulate barrier function - particularly the leak pathway for larger solutes - in epithelia. Therefore, we aimed to precisely define its role in macromolecule passage at single cell-cell junctions. A combination of varying occludin expression by transient and stable knockdown including systematic seeding strategies was employed to achieve a broad and defined pattern of variance in occludin expression over epithelia. This variance model enabled us to examine occludin function in the leak pathway using global and local analysis, i.e. to analyze macromolecule flux across epithelia and macromolecule passage at single-cell level. Macromolecular flux was found not to correlate with occludin expression in intestinal epithelial cells. In fact, by spatially resolving macromolecular permeation sites using a recently developed method we uncovered leaky cell junctions at the edge of Transwells resulting in increased passage. This demonstrates that rare leaks can determine net flux of macromolecules across epithelia while the vast majority of cellular junctions do not contribute significantly. Hence, concomitant local analysis of macromolecule passage across epithelial barriers is indispensable for interpretation of global flux data. By combining this new approach with cell culture models of the leak pathway, we can present evidence that lack of occludin is not sufficient to stimulate the epithelial leak pathway.
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http://dx.doi.org/10.1080/21688370.2019.1608759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619991PMC
July 2020

Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.

Brain 2019 05;142(5):1227-1241

Neuroscience Laboratory and Neurology Clinics, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus.

Charcot-Marie-Tooth disease type 4C is the most common recessively inherited demyelinating neuropathy that results from loss of function mutations in the SH3TC2 gene. Sh3tc2-/- mice represent a well characterized disease model developing early onset progressive peripheral neuropathy with hypo- and demyelination, slowing of nerve conduction velocities and disturbed nodal architecture. The aim of this project was to develop a gene replacement therapy for treating Charcot-Marie-Tooth disease type 4C to rescue the phenotype of the Sh3tc2-/- mouse model. We generated a lentiviral vector LV-Mpz.SH3TC2.myc to drive expression of the human SH3TC2 cDNA under the control of the Mpz promoter specifically in myelinating Schwann cells. The vector was delivered into 3-week-old Sh3tc2-/- mice by lumbar intrathecal injection and gene expression was assessed 4-8 weeks after injection. Immunofluorescence analysis showed presence of myc-tagged human SH3TC2 in sciatic nerves and lumbar roots in the perinuclear cytoplasm of a subset of Schwann cells, in a dotted pattern co-localizing with physiologically interacting protein Rab11. Quantitative PCR analysis confirmed SH3TC2 mRNA expression in different peripheral nervous system tissues. A treatment trial was initiated in 3 weeks old randomized Sh3tc2-/- littermate mice which received either the full or mock (LV-Mpz.Egfp) vector. Behavioural analysis 8 weeks after injection showed improved motor performance in rotarod and foot grip tests in treated Sh3tc2-/- mice compared to mock vector-treated animals. Moreover, motor nerve conduction velocities were increased in treated Sh3tc2-/- mice. On a structural level, morphological analysis revealed significant improvement in g-ratios, myelin thickness, and ratios of demyelinated fibres in lumbar roots and sciatic nerves of treated Sh3tc2-/- mice. Finally, treated mice also showed improved nodal molecular architecture and reduction of blood neurofilament light levels, a clinically relevant biomarker for axonal injury/degeneration. This study provides a proof of principle for viral gene replacement therapy targeted to Schwann cells to treat Charcot-Marie-Tooth disease type 4C and potentially other similar demyelinating inherited neuropathies.
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http://dx.doi.org/10.1093/brain/awz064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487329PMC
May 2019

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Transl Psychiatry 2019 02 4;9(1):75. Epub 2019 Feb 4.

Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.

Preclinical studies point to a pivotal role of the orexin 1 (OX) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10), particularly in the female subsample (p = 9.8 × 10). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
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http://dx.doi.org/10.1038/s41398-019-0415-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361931PMC
February 2019

Approval of First CAR-Ts: Have we Solved all Hurdles for ATMPs?

Cell Med 2019 22;11:2155179018822781. Epub 2019 Jan 22.

Shire, Zug, Switzerland.

T cells are known as the most potent killer cells of the immune system, designed by nature to prevent unwanted challenges. The first class of therapeutic products harnessing the power of T cells for target-specific treatment of oncological diseases was bispecific antibodies. The first T-cell engaging bispecific antibodies that obtained approval were catumaxomab and blinatumomab. Eight years later, the first chimeric antigen receptor (CAR)-T cells received regulatory approval. CAR-T cells are the cellular interpretation of T-cell engaging therapies and have shown remarkable clinical results. CAR-T cells belong to the regulatory group of advanced therapy medicinal products (ATMPs). Due to the cell-/gene-based complex nature, ATMPs are far more challenging to develop than other, more defined, medicinal products. Despite very encouraging clinical results, there have been many set-backs in the development of ATMPs during the past 20 years. Therefore, the approval of the first two CAR-Ts KYMRIAH and YESCARTA is highly encouraging for the field. In this article we review the current landscape of CAR-Ts as a special class of ATMPs. This comprises the pathway to approval including the use of dedicated regulatory tools and challenges that were faced during the procedure. Furthermore, we highlight important future trends in the field.
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http://dx.doi.org/10.1177/2155179018822781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343443PMC
January 2019

Susceptibility to others' emotions moderates immediate self-reported and biological stress responses to witnessing trauma.

Behav Res Ther 2018 11 12;110:55-63. Epub 2018 Sep 12.

Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.

Background: The peri-traumatic stress response is a strong predictor of symptom development after trauma exposure. Regarding witnessing trauma, the stress response might depend on the susceptibility to others' emotions (emotional contagion, EC). This study investigated whether EC moderates the immediate stress response using a trauma film paradigm.

Methods: Ninety-five healthy participants were randomly exposed to a trauma or a neutral film. Perceived stressfulness of the film and pre-to post-film changes in self-reported anxiety, heart rate and saliva cortisol levels were assessed. EC towards negative and positive emotions was measured using the emotional contagion scale and its emotion-specific subscales.

Results: Overall, the trauma film was perceived as distressing and elicited an increase in self-reported anxiety, heart rate and saliva cortisol levels relative to the neutral film. EC towards negative emotions was positively related to the perceived stressfulness of the film, increased anxiety and increased heart rate. The association with saliva cortisol levels was also in the expected direction, but not statistically significant. These associations were not found for EC towards positive emotions.

Discussion: EC towards negative emotions may be an important predictor of trauma exposure outcomes. Further research should clarify its specific contribution in witnessing and undergoing trauma.
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http://dx.doi.org/10.1016/j.brat.2018.09.001DOI Listing
November 2018

The role of childhood trauma and stress reactivity for increased alcohol craving after induced psychological trauma: an experimental analogue study.

Psychopharmacology (Berl) 2018 Oct 10;235(10):2883-2895. Epub 2018 Sep 10.

Department of Psychology, Faculty of Human Science, Medical School Hamburg, Hamburg, Germany.

Background: Traumatic events are associated with alcohol use problems with increased alcohol craving as a potential mediator. There is still a lack of knowledge regarding the causal nature of this association and its underlying mechanisms. This study investigated the effects of acute trauma exposure on alcohol craving in healthy individuals considering the role of stress reactivity and childhood trauma (CT) using a laboratory randomized controlled design.

Methods: Ninety-five healthy participants were randomly exposed to a trauma or a neutral film. History of CT, and pre- to post-film changes in craving (craving reactivity, CR), anxiety, skin conductance, heart rate, and saliva cortisol levels were assessed. Moreover, associations between trauma film exposure and CR, the moderating role of CT, and associations between CT, stress reactivity, and trauma-induced CR were analyzed.

Results: Relative to the neutral film, the trauma film elicited an increase in CR in females but not in males. In males but not in females, the association between trauma film exposure and CR was moderated by CT, with trauma-induced CR increasing with the number of CT. In males, CT was related to decreased cortisol reactivity and increased heart rate and skin conductance response of which skin conductance was also associated with CR.

Discussion: These findings provide further evidence for a causal link between traumatic experiences and CR. While this association seems to be stronger in females, males might still be at risk in case of other vulnerability factors such as CT, with altered sympathetic stress reactivity as a potential contributing mechanism.
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http://dx.doi.org/10.1007/s00213-018-4979-4DOI Listing
October 2018

The Startle-Evoked Potential: Negative Affect and Severity of Pathology in Anxiety/Mood Disorders.

Biol Psychiatry Cogn Neurosci Neuroimaging 2018 07 8;3(7):626-634. Epub 2017 Aug 8.

Center for the Study of Emotion and Attention, University of Florida, Gainesville, Florida.

Background: The National Institute of Mental Health Research Domain Criteria initiative encourages a search for dimensional biological measures of psychopathology unconstrained by current diagnostic categories. Consistent with this aim, the presented research studies a large sample of anxiety and mood disorder patients, assessing differences in principal diagnoses and comorbidity patterns, clinicians' ratings, and questionnaire measures of negative affect and life dysfunction as they relate to a potential brain marker of pathology: the amplitude of the event-related potential (ERP) elicited by a startle-evoking stimulus.

Methods: Patients seeking evaluation or treatment for anxiety and mood disorders (N = 208) participated in two tasks at the University of Florida (Gainesville, FL): 1) imagining emotional and neutral events and 2) viewing emotional and neutral pictures while acoustic startle probes were presented and the ERP was recorded. For a comparison patient group (N = 120), startle probes were administered and ERPs recorded at the University of Greifswald (Greifswald, Germany) while performing the same imagery task.

Results: Reduced positive amplitude of a centroparietal startle-evoked ERP (156-352 ms after onset) significantly predicted higher questionnaire scores of anxiety/depression, reports of increased life dysfunction, greater comorbidity, and clinician ratings of heightened severity and poorer prognosis. The effect was general across principal diagnoses, found for both the Florida and German samples, and consistent in pattern despite differences in the tasks administered.

Conclusions: The startle-evoked ERP reliably predicts severity and breadth of psychopathology, independent of task context. It is a potential significant contributor to a needed array of biological measures that might improve classification of anxiety and mood disorders.
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http://dx.doi.org/10.1016/j.bpsc.2017.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063515PMC
July 2018

The Sandwich Assay: A Method for Subcellular Visualization of Paracellular Macromolecule Passage in Epithelial Sheets.

Curr Protoc Cell Biol 2018 03;78(1):20.10.1-20.10.13

Institute of Anatomy II, Jena University Hospital, Jena, Germany.

To date, the permeability of epithelia to larger solutes (greater than ∼4 Å in diameter) has been analyzed by flux measurements using various tracers that cannot spatially resolve the permeation sites. This unit describes a method for localizing such sites of passage in epithelial sheets with subcellular resolution. The method makes use of avidin as a basolateral capture probe in epithelial monolayers or mucosae to unmask the passage of biotinylated and fluorophore-labeled tracer molecules as they go through the junctional barrier. Once bound to avidin, the tracers are immobilized at the site of a barrier leak. The localization, the distribution, and the extent of passage are eventually evaluated by imaging. The assay detects single leaks and is hence able to spatially resolve rarely occurring changes. It is also modular and flexible to use with various macromolecular tracers, and its sensitivity is adjustable. If designed as a chase experiment, the method allows for analysis of temporal barrier openings. If performed at low temperatures, this assay will block transcellular passage and, combined with global flux measurement, unambiguously determine paracellular passage. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cpcb.42DOI Listing
March 2018
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