Publications by authors named "Carolin Hoyer"

52 Publications

Central retinal artery occlusion as a neuro-ophthalmological emergency: the need to raise public awareness.

Eur J Neurol 2021 Jan 16. Epub 2021 Jan 16.

Department of Neurology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany.

Background And Purpose: Central retinal artery occlusion (CRAO) is a neuro-ophthalmological emergency necessitating adequate and comprehensive diagnosis. Its optimal management and treatment, however, are still under debate. This study aimed at identifying respective areas for improvement.

Methods: We retrospectively analysed the medical records of patients with CRAO treated in our stroke unit between January 2016 and August 2020.

Results: During the observational period, 101 patients with CRAO were admitted. We observed an increase in the rate of patients primarily admitted to the stroke unit from 52.2% to 97.4%. In addition, the thrombolysis rate - with thrombolysis performed on an individual basis - rose from 0% to 14.1%, coinciding with the implementation of an in-hospital management guideline. Almost 60% of all patients presented outside of the 4.5-h time window for thrombolysis; by far the most common reason not to deliver intravenous thrombolysis in our cohort was a prehospital delay to presentation (58.8%), with 44.4% of patients having consulted a private-practice ophthalmologist first. A total of 25 (32.5%) of 77 patients who underwent magnetic resonance imaging (MRI) had accompanying acute ischaemic stroke lesions on diffusion-weighted MRI of the brain. A possible aetiology of CRAO was identified in 41.4% of patients.

Discussion: Public awareness of sudden unilateral visual loss as a presenting sign for stroke should be raised, increasing the chances for timely recognition in a hospital with ophthalmological expertise and a stroke centre. This is essential for ongoing and future prospective trials on this subject.
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http://dx.doi.org/10.1111/ene.14735DOI Listing
January 2021

Decreased admissions and change in arrival mode in patients with cerebrovascular events during the first surge of the COVID-19 pandemic.

Neurol Res Pract 2020 16;2:47. Epub 2020 Nov 16.

Department of Neurology and Mannheim Center for Translational Neuroscience, Heidelberg University, Medical Faculty Mannheim, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany.

Background And Purpose: Investigating clinical characteristics of patients presenting with cerebrovascular events during the pandemic may provide valuable insight into further understanding the phenomenon of decreased stroke admissions during the COVID-19 pandemic.

Method: Data of patients presenting with a cerebrovascular event to the emergency department during weeks 12-17/2020 were compared to data from the respective weeks in 2019.

Results: A significant reduction in the number of admissions by 35.9% ( = 0.005) was observed during the COVID-19 epoch. In addition, significantly more patients arrived by ambulance during the COVID-19 epoch (2019: 75.7%, 2020: 94.2%;  = 0.001).

Conclusion: Our data may have implications as to how campaigns raising awareness for serious medical conditions in the context of the pandemic should be framed.
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http://dx.doi.org/10.1186/s42466-020-00094-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668014PMC
November 2020

Changes in Demographic and Diagnostic Spectra of Patients with Neurological Symptoms Presenting to an Emergency Department During the COVID-19 Pandemic: A Retrospective Cohort Study.

Neuropsychiatr Dis Treat 2020 30;16:2221-2227. Epub 2020 Sep 30.

Department of Neurology, Medical Faculty Mannheim and Mannheim Center for Translational Neurosciences (MCTN), Heidelberg University, Mannheim, Germany.

Objective: To analyse the characteristics of patients with neurological complaints seeking evaluation in an interdisciplinary emergency department (ED) during the rise of the COVID-19 pandemic in Germany.

Methods: In this retrospective study, data on the number of ED presentations due to neurological complaints in weeks 1-15/2020 were collected. In addition, hospital chart data of patients referred for neurological evaluation during weeks 12-15/2020 when the pandemic began impacting on public life in Germany were analysed regarding demographic information, chief complaints, modes of presentation and disposition and ED discharge diagnosis. Both data sets were compared to respective periods from 2017.

Results: During the surge of COVID-19, we found a significant decrease of the total number of neurological ED patients by 47.6%. Comparing weeks 12-15 of 2017 and 2020, we found a decrease in the number of patients of <30 years (p<0.001) and an increase of those 70 years (p<0.001). A higher proportion of patients were admitted to escalated care (p=0.03), and fewer patients were discharged against medical advice (p<0.001). In addition, the ratio of less acute diagnoses (eg, benign headaches) declined significantly.

Conclusion: Our findings suggest that the pandemic has contributed to a - potentially transient - reframing of laypeople's perception of urgency and necessity for emergency presentation. The establishment and promotion of health-care structures and services like telemedical consultations and the creation of safe ED environments will be essential to enable adequate delivery of care in potential future waves of the pandemic.
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http://dx.doi.org/10.2147/NDT.S273913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535112PMC
September 2020

Diffusion-weighted MRI in transient global amnesia and its diagnostic implications.

Neurology 2020 07 12;95(2):e206-e212. Epub 2020 Jun 12.

From the Department of Neurology (K.S., C.H., R.G., M.G., A.E., M.P., A.G.), Mannheim Center of Translational Neuroscience, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany; and Department of Neurology (L.R.C.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Objective: To analyze how the evidence of hippocampal diffusion-weighted imaging (DWI) lesions may support the clinical diagnosis of transient global amnesia (TGA).

Methods: In this retrospective observational study, 390 consecutive patients with isolated TGA were analyzed, who were evaluated at our institution between July 1999 and August 2018. The size, location, and number of lesions and time-dependent lesion detectability were examined. The incidence of DWI lesions was reviewed with regard to different levels of clinical diagnostic certainty upon presentation to the emergency department.

Results: Hippocampal DWI lesions were detected in 272 (70.6%) patients with TGA, with a mean of 1.05 ± 0.98 (range 0-6) and a mean lesion size of 4.01 ± 1.22 mm (range 1.7-8.6 mm). In the subgroups of lower diagnostic certainty (amnesia witnessed by layperson or self-reported amnestic gap), DWI was helpful in supporting the diagnosis of TGA in 76 (69.1%) patients. In 187 patients with information about the exact onset, DWI lesions were analyzed in relation to latency between onset and MRI. Lesions could be detected at all time points and up to 6 days after symptom onset in individual patients; the highest rate of DWI-positive MRI (93%) was in the 12-24 hours time window.

Conclusion: MRI findings can support the diagnosis of TGA and may be particularly valuable in situations of low clinical certainty. DWI-ideally performed with a minimum delay of 20 hours after onset-should therefore be considered a useful adjunct to the diagnosis of TGA.
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http://dx.doi.org/10.1212/WNL.0000000000009783DOI Listing
July 2020

Decreased utilization of mental health emergency service during the COVID-19 pandemic.

Eur Arch Psychiatry Clin Neurosci 2020 Jun 9. Epub 2020 Jun 9.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

During the rapid rise of the COVID-19 pandemic, a reduction of the numbers of patients presenting to emergency departments has been observed. We present an early study from a German psychiatric hospital to assess the dynamics of mental health emergency service utilization rates during the COVID-19 pandemic. Our results show that the numbers of emergency presentations decreased, and a positive correlation between these numbers and mobility of the general public suggests an impact of extended measures of social distancing. This finding underscores the necessity of raising and sustaining awareness regarding the threat to mental health in the context of the pandemic.
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http://dx.doi.org/10.1007/s00406-020-01151-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282463PMC
June 2020

Acute Stroke in Times of the COVID-19 Pandemic: A Multicenter Study.

Stroke 2020 07 9;51(7):2224-2227. Epub 2020 Jun 9.

Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Germany (C. Hoyer, A.E., M.P., K.S.).

Background And Purpose: This study aims to assess the number of patients with acute ischemic cerebrovascular events seeking in-patient medical emergency care since the implementation of social distancing measures in the coronavirus disease 2019 (COVID-19) pandemic.

Methods: In this retrospective multicenter study, data on the number of hospital admissions due to acute ischemic stroke or transient ischemic attack and numbers of reperfusion therapies performed in weeks 1 to 15 of 2020 and 2019 were collected in 4 German academic stroke centers. Poisson regression was used to test for a change in admission rates before and after the implementation of extensive social distancing measures in week 12 of 2020. The analysis of anonymized regional mobility data allowed for correlations between changes in public mobility as measured by the number and length of trips taken and hospital admission for stroke/transient ischemic attack.

Results: Only little variation of admission rates was observed before and after week 11 in 2019 and between the weeks 1 and 11 of 2019 and 2020. However, reflecting the impact of the COVID-19 pandemic, a significant decrease in the number of admissions for transient ischemic attack was observed (-85%, -46%, -42%) in 3 of 4 centers, while in 2 of 4 centers, stroke admission rates decreased significantly by 40% and 46% after week 12 in 2020. A relevant effect on reperfusion therapies was found for 1 center only (thrombolysis, -60%; thrombectomy, -61%). Positive correlations between number of ischemic events and mobility measures in the corresponding cities were identified for 3 of 4 centers.

Conclusions: These data demonstrate and quantify decreasing hospital admissions due to ischemic cerebrovascular events and suggest that this may be a consequence of social distancing measures, in particular because hospital resources for acute stroke care were not limited during this period. Hence, raising public awareness is necessary to avoid serious healthcare and economic consequences of undiagnosed and untreated strokes and transient ischemic attacks.
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http://dx.doi.org/10.1161/STROKEAHA.120.030395DOI Listing
July 2020

Comparing Expert and Non-Expert Assessment of Patients Presenting with Neurological Symptoms to the Emergency Department: A Retrospective Observational Study.

Neuropsychiatr Dis Treat 2020 13;16:447-456. Epub 2020 Feb 13.

Department of Neurology, UniversitätsMedizin Mannheim, Heidelberg University, Mannheim, Germany.

Objective: Referrals to neurology in emergency departments (ED) are continuously increasing, currently representing 15% of all admissions. Existing triage systems were developed for general medical populations and have not been validated for patients with neurological symptoms.

Methods: To characterize neurological emergencies, we first retrospectively analyzed symptoms, service times and resources of the cohort of neurological referrals to a German interdisciplinary ED (IED) during 2017 according to urgency determined by final IED diagnosis. In a second step, we performed a retrospective assignment of consecutive patients presenting in April 2017 according to internal guidelines as either acute (requiring diagnostic/therapeutic procedures within 24 hrs) or non-acute neurological conditions as well as a retrospective classification according to the Emergency Severity Index (ESI). Both assessments were compared with the urgency according to the final ER diagnosis.

Results: In a 12-month period, 36.4% of 5340 patients were rated as having an urgent neurological condition; this correlated with age, door-to-doctor time, imaging resource use and admission (p < 0.001, respectively). In a subset of 275 patients, 59% were retrospectively triaged as acute according to neurological expertise and 48% according to ESI categories 1 and 2. Neurological triage identified urgency with a significantly higher sensitivity (94.8, p < 0.01) but showed a significantly lower specificity (55.1, p < 0.05) when compared to ESI (80.5 and 65.2, respectively).

Conclusion: The ESI may not take specific aspects of neurological emergency (eg, time-sensitivity) sufficiently into account. Refinements of existing systems or supplementation with dedicated neurological triage tools based on neurological expertise and experience may improve the triage of patients with neurological symptoms.
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http://dx.doi.org/10.2147/NDT.S236160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025652PMC
February 2020

The novel seizure quality index for the antidepressant outcome prediction in electroconvulsive therapy: association with biomarkers in the cerebrospinal fluid.

Eur Arch Psychiatry Clin Neurosci 2020 Oct 23;270(7):911-919. Epub 2019 Nov 23.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.

For patients with depression treated with electroconvulsive therapy (ECT), the novel seizure quality index (SQI) can predict the risk of non-response (and non-remission)-as early as after the second ECT session-based the extent of several ictal parameters of the seizure. We aim to test several CSF markers on their ability to predict the degree of seizure quality, measured by the SQI to identify possible factors, that could explain some variability of the seizure quality. Baseline CSF levels of metabolites from the kynurenine pathway, markers of neurodegeneration (tau proteins, β-amyloids and neurogranin), elements of the innate immune system, endocannabinoids, sphingolipids, neurotrophic factors (VEGF) and Klotho were measured before ECT in patients with depression (n = 12) to identify possible correlations with the SQI by Pearson's partial correlation. Negative, linear relationships with the SQI for response were observed for CSF levels of T-tau (r = - 0.69, p = 0.019), phosphatidylcholines (r = - 0.52, p = 0.038) and IL-8 (r = - 0.67, p = 0.047). Regarding the SQI for remission, a negative, linear relationship was noted with CSF levels of the endocannabinoid AEA (r = - 0.70, p = 0.024) and CD163 (r = - 0.68, p = 0.029). In sum, CSF Markers for the innate immune system, for neurodegeneration and from lipids were found to be associated with the SQI for response and remission after adjusting for age. Consistently, higher CSF levels of the markers were always associated with lower seizure quality. Based on these results, further research regarding the mechanism of seizure quality in ECT is suggested.
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http://dx.doi.org/10.1007/s00406-019-01086-xDOI Listing
October 2020

The use of a dedicated neurological triage system improves process times and resource utilization: a prospective observational study from an interdisciplinary emergency department.

Neurol Res Pract 2019 25;1:29. Epub 2019 Oct 25.

Department of Neurology, UniversitätsMedizin Mannheim, Heidelberg University, Medical Faculty, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany.

Background: Patients with neurological symptoms have been contributing to the increasing rates of emergency department (ED) utilization in recent years. Existing triage systems represent neurological symptoms rather crudely, neglecting subtler but relevant aspects like temporal evolution or associated symptoms. A designated neurological triage system could positively impact patient safety by identifying patients with urgent need for medical attention and prevent inadequate utilization of ED and hospital resources.

Methods: We compared basic demographic information, chief complaint/presenting symptom, door-to-doctor time and length of stay (LOS) as well as utilization of ED resources of patients presenting with neurological symptoms or complaints during a one-month period before as well as after the introduction of the Heidelberg Neurological Triage System (HEINTS) in our interdisciplinary ED. In a second step, we compared diagnostic and treatment processes for both time periods according to assigned acuity.

Results: During the two assessment periods, 299 and 300 patients were evaluated by a neurologist, respectively. While demographic features were similar for both groups, overall LOS ( < 0.001) was significantly shorter, while CT ( = 0.023), laboratory examinations ( = 0.006), ECG ( = 0.011) and consultations ( = 0.004) were performed significantly less often when assessing with HEINTS. When considering acuity, an epileptic seizure was less frequently evaluated as acute with HEINTS than in the pre-HEINTS phase ( = 0.002), while vertigo patients were significantly more often rated as acute with HEINTS ( < 0.001). In all cases rated as acute, door-to-doctor-time (DDT) decreased from 41.0 min to 17.7 min ( < 0.001), and treatment duration decreased from 304.3 min to 149.4 min ( < 0.001) after introduction of HEINTS triage.

Conclusion: A dedicated triage system for patients with neurological complaints reduces DDT, LOS and ED resource utilization, thereby improving ED diagnostic and treatment processes.
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http://dx.doi.org/10.1186/s42466-019-0036-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650056PMC
October 2019

Uncompleted emergency department care and discharge against medical advice in patients with neurological complaints: a chart review.

BMC Emerg Med 2019 10 11;19(1):52. Epub 2019 Oct 11.

Department of Neurology, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68135, Mannheim, Germany.

Background: Uncompleted emergency department care and against-medical-advice discharge represent relevant medical problems with impact on patient safety and potential medicolegal and socioeconomic consequences. They may also indicate structural or procedural problems in the emergency department (ED) relating to patient management and flow. While patients with neurological complaints frequently leave the ED against medical advice or without being seen, no dedicated analysis of this group of patients aiming at the identification of characteristics associated with irregular ED discharge has been performed so far.

Methods: A chart review was performed of all patients with neurological complaints presenting to a German interdisciplinary emergency department between January and December 2017 for neurological evaluation. Demographics, mode of presentation, process times, presenting symptoms and diagnosis were recorded. Patients leaving against medical advice after an informed consent discussion and signing of documentation (DAMA) or leaving prematurely without notifying ED staff (PL) were compared to the total of patients who were admitted or discharged (non-DAMA/PL).

Results: Of all patients presenting with neurological symptoms or complaints, 3% left against medical advice and 2.2% left prematurely. DAMA/PL patients were younger (p < .001), and they were more frequently self-presenting (p < 0.001). Headaches, seizures and sensory deficits were the most frequent presenting symptoms in DAMA/PL patients, and 56.1% of those presenting with a seizure had a history of epilepsy. The most common documented reason for leaving was the duration of door-to-doctor time.

Conclusions: Younger age, self-presenting mode of presentation and presentation with headache, seizures or sensory deficits are associated with premature leave or against-medical-advice discharge of patients with neurological complaints from the ED, and long waiting times were given as the major reason for leaving the ED. Increasing ED staff's awareness of these factors and the optimization of pre-hospital assessment and demand management, thereby positively impacting on patient flow and ED process times, may help to prevent irregular discharges from the ED.
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http://dx.doi.org/10.1186/s12873-019-0273-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788079PMC
October 2019

Optimization of Insect Odorant Receptor Trafficking and Functional Expression Via Transient Transfection in HEK293 Cells.

Chem Senses 2019 10;44(9):673-682

Department of Evolutionary Neuroethology, Max Planck Institute for Chemical Ecology, Jena, Germany.

Insect odorant receptors (ORs) show a limited functional expression in various heterologous expression systems including insect and mammalian cells. This may be in part due to the absence of key components driving the release of these proteins from the endoplasmic reticulum and directing them to the plasma membrane. In order to mitigate this problem, we took advantage of small export signals within the human HCN1 and Rhodopsin that have been shown to promote protein release from the endoplasmic reticulum and the trafficking of post-Golgi vesicles, respectively. Moreover, we designed a new vector based on a bidirectional expression cassette to drive the functional expression of the insect odorant receptor coreceptor (Orco) and an odor-binding OR, simultaneously. We show that this new method can be used to reliably express insect ORs in HEK293 cells via transient transfection and that is highly suitable for downstream applications using automated and high-throughput imaging platforms.
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http://dx.doi.org/10.1093/chemse/bjz062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821309PMC
October 2019

Impact of psychiatric comorbidity on the severity, short-term functional outcome, and psychiatric complications after acute stroke.

Neuropsychiatr Dis Treat 2019 4;15:1823-1831. Epub 2019 Jul 4.

Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.

Background And Purpose: The comorbidity of psychiatric disorders and cerebrovascular disease appears to be complex with underlying bidirectional influences. Hitherto, research has focused mainly on the evaluation of stroke risk in particular psychiatric disorders; only a few studies have assessed their role in the acute natural history of stroke. The aim of this study was to provide a perspective on psychiatric premorbidity and its impact on stroke severity, psychiatric complications during the initial treatment phase, and the short-term functional outcome of stroke.

Patients And Methods: We retrospectively studied the impact of a predocumented psychiatric diagnosis (PDPD) on stroke severity, short-term functional outcome, and psychiatric complications in a sample of 798 patients consecutively admitted for acute ischemic or hemorrhagic stroke by performing a chart review. Group comparisons (PDPD vs non-PDPD) with adjustment for covariates were carried out either using multivariate analysis of variance or logistic regression analysis.

Results: More severe strokes (ie, mean National Institute of Health Stroke Scale score on admission 10.1±7.9 vs 7.5±7.4; F(10,796)=18.5, <0.0001) and higher prevalence of poor outcome (73.7 vs 54.9%; OR: 2.6, standard error: 0.5, z=4.82, <0.0001) was found in patients with a documented psychiatric diagnosis at the time of stroke, as well as a higher rate of psychiatric complications during the initial treatment phase (46.7 vs 28.9%; OR: -0.78, z=4.59, <0.0001).

Conclusion: Our data have clinical implications in that they call for identification of psychiatric premorbidity or comorbidity through careful history-taking and particularly close monitoring for psychiatric complications with respect to their potentially negative impact on outcome after stroke.
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http://dx.doi.org/10.2147/NDT.S206771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614829PMC
July 2019

Cytokine-mediated cellular immune activation in electroconvulsive therapy: A CSF study in patients with treatment-resistant depression.

World J Biol Psychiatry 2020 02 31;21(2):139-147. Epub 2019 May 31.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Evidence points towards an important relationship between the antidepressant effects of electroconvulsive therapy (ECT) and the modulation of the immune system. To further elucidate this interplay, we performed a study on the effects of the antidepressant treatment by ECT on 25 cytokines in patients with depression. We measured 25 different cytokines (interleukin (IL)-1β, IL-1RA, Il-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17, tumor necrosis factor-α, interferon (IFN)-α, IFN-γ, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein (MIP)-1α, MIP-1β, IFN-γ-induced protein 10 (IP-10), monokine induced by IFN-γ, Eotaxin, Rantes and monocyte chemoattractant protein 1) in the cerebrospinal fluid (CSF) and blood of 12 patients with a severe and treatment-resistant depressive episode before and after a course of ECT. CSF levels of IP-10, IL-5 and IL-8 were elevated after ECT and more ECT sessions were associated with the differences of CSF levels before and after ECT of IFN-γ, IL-2RA, Rantes, IL-6 and IL-1β. Responders and/or remitters had a decrease of CSF levels of IL-17, MIP-1α, Rantes and IL-2R during ECT. CSF IP-10 levels increased less during ECT in patients who had a remission. Although the sample size was small, we found different effects of the ECT treatment per se and of the antidepressant action induced by ECT in CSF and blood.
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http://dx.doi.org/10.1080/15622975.2019.1618494DOI Listing
February 2020

Peripheral levels of the anti-aging hormone Klotho in patients with depression.

J Neural Transm (Vienna) 2019 06 4;126(6):771-776. Epub 2019 May 4.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.

Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associated with accelerated cellular aging as well as aging-related phenotypes and comorbidity observed in Klotho deficiency. Soluble α-Klotho (sKlotho) serum levels in patients with a major depressive episode and either undergoing electroconvulsive therapy (n = 16) or a monotherapy with an antidepressant (n = 37) were investigated. We measured the sKlotho serum levels in those patients before and after treatment and compared the baseline levels with those of age-matched healthy controls (n = 39). No group differences were found between the baseline sKlotho levels of patients and controls (573.5 pg/ml vs. 563.8 pg/ml; p = 0.80) and between pre- and post-treatment in the patients with depression (563.8 pg/ml vs. 561.8 pg/ml; p = 0.15), when treated either with electroconvulsive therapy or antidepressant. The major limitation of our study might be that peripheral material such as serum might not reliably reflect processes in the central nervous system. In sum, this first study on peripheral sKlotho levels in a clinical sample cannot confirm a global Klotho dysregulation in depression as it has been already suggested by others. Nonetheless, further preclinical and clinical studies on the involvement of Klotho in affective disorders should be carried out.
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http://dx.doi.org/10.1007/s00702-019-02008-wDOI Listing
June 2019

Isolable Cu(I) Complexes of Extremely Electron-Poor, Completely Unreduced o-Quinone and "Di- o-Quinone" Ligands Stabilized through π-π Interactions in the Secondary Coordination Sphere.

Inorg Chem 2019 Mar 25;58(6):3754-3763. Epub 2019 Feb 25.

Institut für Chemie und Biochemie, Anorganische Chemie , Freie Universität Berlin , Fabeckstrasse 34-36 , 14195 Berlin , Germany.

The copper-quinone interaction plays important roles in diverse fields such as biochemistry, catalysis, and optically/magnetically switchable materials. Despite this fact, the isolation and thorough characterization of copper(I)-quinone complexes remains a highly challenging task owing to their intrinsic instability. We herein present systems where the stability imparted by the extended π-system of a pyrene ring is used to synthesize, isolate, and crystallographically characterize the first example of a dinuclear metal complex that is bridged by a completely unreduced "di- o-quinone"-type ligand. Additionally, we present the monocopper counterpart with the o-quinone-pyrene type of ligand. The copper complexes are redox-rich and display intriguing electrochemical, optical, and electron paramagnetic resonance (EPR) spectroscopic properties. The line-rich EPR spectra of the one-electron reduced copper(I) complexes were simulated and analyzed via density functional theory calculations. The results presented here establish π-π stacking as a viable alternative to stabilize otherwise unstable redox-active compounds with possible consequences for sensing and redox catalysis.
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http://dx.doi.org/10.1021/acs.inorgchem.8b03362DOI Listing
March 2019

Biomarkers for Antidepressant Efficacy of Electroconvulsive Therapy: An Exploratory Cerebrospinal Fluid Study.

Neuropsychobiology 2019 17;77(1):13-22. Epub 2018 Aug 17.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.

Background: No candidate biomarkers based on cerebrospinal fluid (CSF) have been identified as prognostic factors in patients with major depression treated with electroconvulsive therapy (ECT), yet.

Method: Following different underlying hypotheses, we analysed baseline CSF levels of markers of neurodegeneration (tau proteins, β-amyloids and neurogranin), elements of the innate immune system (interleukin [IL]-6, neopterin, soluble CD14, soluble CD163, migration inhibitory factor and monocyte chemotactic protein 1), endocannabinoids, sphingolipids and Klotho before ECT in patients with depression (n = 12) to identify possible correlations with the clinical antidepressant response to ECT.

Results: Correlation with the reduction of the depressive symptoms could be observed especially for markers of neurodegeneration and elements of the innate immune system. Differences for CSF levels of several markers were found between the groups of responders and non-responders at the trend level.

Limitations: The sample size is small and the -distribution of responders and non-responders is uneven.

Conclusions: It is this first study on CSF biomarkers for antidepressant efficacy of ECT warrants further research regarding the mechanism of ECT and personalized antidepressant therapy.
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http://dx.doi.org/10.1159/000491401DOI Listing
December 2018

A novel Seizure Quality Index based on ictal parameters for optimizing clinical decision making in electroconvulsive therapy. Part 1: development.

Eur Arch Psychiatry Clin Neurosci 2018 Dec 6;268(8):819-830. Epub 2018 Jun 6.

Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health, Heidelberg University, J5, 68159, Mannheim, Germany.

Early identification of patients at high risk for an unfavorable outcome to ECT during the course might be beneficial because it provides an opportunity for timely intensification or optimization of stimulus conditions. We aimed to develop a new Seizure Quality Index (SQI) that delivers a clinical relevant outcome prediction early in the treatment course and can be used within common clinical setting. An observational study was conducted. Patients (n = 86) with a depressive episode and the clinical decision for ECT (right unilateral, brief pulse) were included, and several ictal parameters derived from the second ECT session and the clinical outcome of the patients were documented. Optimal cut-off points for five different domains of ictal adequacy for younger and older patients for the prediction of "non-response" and "non-remission" based on seizure quality was determined by the Youden Index and a sum score was built. Logistic regression analyses tested the predictive power of derived models. For both outcome variables "non-response" and "non-remission", the logistic regression models were statistically significant, albeit for remission only for subjects below the age of 65 years (χ = 17.9, p = 0.001) and (χ = 6.4, p = 0.020), respectively. The models correctly classified 87.2% (non-response) and 50.0% (non-remission) of the cases. ROC curve analysis showed an AUC of 0.87 (non-response) and 0.70 (non-remission). In elderly patients (> 65), no such model could be established due to a response rate of 100%. Our data provide promising, clinically relevant results about the prediction of response to ECT at an early stage for patients with depression.
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http://dx.doi.org/10.1007/s00406-018-0910-6DOI Listing
December 2018

Impact of pre-admission treatment with non-vitamin K oral anticoagulants on stroke severity in patients with acute ischemic stroke.

J Thromb Thrombolysis 2018 May;45(4):529-535

Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) have gained increasing importance for stroke prevention in patients with non-valvular atrial fibrillation (AF). With changing prescription practice, among other factors, clinicians can expect to see rising numbers of patients with ischemic stroke and pre-existing NOAC therapy. Few data exist regarding a potential impact of NOAC on stroke severity and outcome.

Aims: To evaluate the impact of pre-admission NOAC therapy on ischemic stroke severity.

Methods: Retrospective analysis of medical data of 376 patients with newly detected AF or known AF with either no pre-admission oral anticoagulation (n = 277) or existing NOAC therapy (n = 99; Apixaban, n = 33, Dabigatran, n = 16; Edoxaban, n = 1; Rivaroxaban, n = 49) consecutively admitted for acute ischemic stroke between January 2015 and December 2016.

Results: Patients with pre-admission NOAC had significantly more often experienced a prior stroke than patients not on NOAC therapy (45.5 vs. 18.4%, p < 0.001) and were significantly more frequently non-smokers (1.0 vs. 7.2%, p = 0.021). Significantly more patients without pre-admission NOAC received thrombolysis (33.8 vs. 8.1%, p < 0.001). Pre-admission NOAC therapy was associated with significantly lower NIHSS and mRS scores upon admission (median NIHSS score 6 vs. 10, p = 0.018, median mRS score 4 vs. 5, p = 0.035) and trend-level lower NIHSS scores at discharge (median NIHSS score 3 vs. 5, p = 0.057). There were no differences regarding the frequency of symptomatic intracerebral hemorrhage between NOAC and non-NOAC patients (p > 0.05).

Conclusions: We report a positive impact of pre-admission NOAC on ischemic stroke severity, which is particularly remarkable in light of the increased prevalence of prior stroke and lower rates of thrombolysis in this patient population.
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http://dx.doi.org/10.1007/s11239-018-1634-1DOI Listing
May 2018

Electroconvulsive therapy enhances the anti-ageing hormone Klotho in the cerebrospinal fluid of geriatric patients with major depression.

Eur Neuropsychopharmacol 2018 03 20;28(3):428-435. Epub 2017 Dec 20.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany. Electronic address:

Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associated with accelerated cellular aging as well as aging-related phenotypes and comorbidity observed in Klotho deficiency. On these grounds we investigated Klotho levels in the cerebrospinal fluid (CSF) and serum of eight geriatric patients undergoing electroconvulsive therapy (ECT) for severe depression. We hypothesize that ECT as a highly effective antidepressant treatment leads enhances Klotho levels. We found a significant difference between pre- and post-ECT CSF Klotho (792.5pg/ml vs. 991.3pg/ml, p=0.0020), but no difference in serum Klotho (602.5 vs. 594.3, p=0.32). Moreover, CSF Klotho increase positively correlated with the number of single ECT sessions that were performed in each patient (F1, 6)=7.84, p=0.031). Conjointly, the results of our exploratory study with a small sample size suggest a central nervous system-specific impact of ECT on Klotho, which may in turn partake in mediating the antidepressant effect of ECT. We suggest the modulation of neuroinflammatory processes, which have been ascribed pathophysiological relevance within the conceptual framework of the neuroinflammation hypothesis of depression, through ECT as a potential mechanism by which Klotho is enhanced in response to treatment. Further preclinical and clinical investigation should aim for a precise identification of the role of Klotho in depressive disorder.
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http://dx.doi.org/10.1016/j.euroneuro.2017.12.012DOI Listing
March 2018

Antidepressant efficacy of electroconvulsive therapy is associated with a reduction of the innate cellular immune activity in the cerebrospinal fluid in patients with depression.

World J Biol Psychiatry 2018 08 9;19(5):379-389. Epub 2017 Aug 9.

a Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim , Heidelberg University , Mannheim , Germany.

Objectives: A bidirectional link between the antidepressant effects of electroconvulsive therapy (ECT) and the modulation of the immune system has been proposed. To elucidate the interplay between antidepressant treatment and macrophage/microglia activation in humans, we performed a study on the effects of the antidepressant treatment by ECT on markers of macrophage/microglia activation in patients with depression.

Methods: We measured six different markers (IL-6, neopterin, sCD14, sCD163 MIF and MCP1) of macrophage/microglia activation in the cerebrospinal fluid (CSF) and blood of 12 patients with a severe, treatment-resistant depressive episode before and after a course of ECT.

Results: Some markers in the CSF of remitters were reduced after the ECT course and differed from non-remitters, but no differences were found before and after ECT independently from the antidepressant efficacy. CSF baseline levels of some markers could predict the reduction of depressive psychopathology during ECT. Higher CSF levels indicating increased macrophage/microglia activation at baseline predicted a better treatment response to ECT.

Conclusions: Although the sample size was small, our data suggest that macrophages/microglia are involved in the pathophysiology of major depression and that antidepressant efficacy by ECT might be partly explained by the modulation of the innate immune system within the brain.
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http://dx.doi.org/10.1080/15622975.2017.1355473DOI Listing
August 2018

HIV-Associated Cerebellar Dysfunction and Improvement with Aminopyridine Therapy: A Case Report.

Case Rep Neurol 2017 May-Aug;9(2):121-126. Epub 2017 May 16.

Department of Neurology, University Medical Centre Mannheim, Mannheim, Germany.

Apart from infectious causes and cerebellar dysfunction associated with acquired immune deficiency syndrome dementia or HIV-associated neurocognitive disorder, cerebellar dysfunction in HIV-positive individuals has been ascribed to granule cell neuronopathy as well as primary cerebellar atrophy without identifiable etiology. We report the case of a patient with progressive cerebellar dysfunction as the primary manifestation of HIV infection. No symptom improvement was seen under combination antiretroviral therapy, which had been established upon diagnosis, but the patient improved rapidly under 4-aminopyridine treatment, which was recommended 1 year later. Our report, adding to the rather small number of reports of HIV-associated cerebellar atrophy and dysfunction as a primary manifestation of HIV infection, draws attention to HIV as a possible differential etiology of a cerebellar syndrome. Further, rapid improvement of symptom severity under 4-aminopyridine treatment warrants further investigation with longer-term follow-up into the effectiveness of this compound in gait disorder associated with HIV infection.
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http://dx.doi.org/10.1159/000475544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471757PMC
May 2017

Electroconvulsive therapy enhances endocannabinoids in the cerebrospinal fluid of patients with major depression: a preliminary prospective study.

Eur Arch Psychiatry Clin Neurosci 2017 Dec 24;267(8):781-786. Epub 2017 Mar 24.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159, Mannheim, Germany.

Despite the lack of clinical data about the role of the endocannabinoid system (ECS) in affective disorders, preclinical work suggests that the ECS is relevant in both with regard to the etiology of depression as well as the mediation of antidepressant effects. We measured the intraindividual levels of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the cerebrospinal fluid of 12 patients suffering from a major depressive episode before and after the antidepressant treatment by electroconvulsive therapy (ECT). AEA was significantly elevated after ECT as compared to baseline. The AEA increase positively correlated with the number of individually performed ECT sessions. Although the sample size was small and confounders were not rigorously controlled for, our finding corroborates preclinical work and should encourage further exploration of the involvement of the ECS in depressive disorder.
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http://dx.doi.org/10.1007/s00406-017-0789-7DOI Listing
December 2017

Electroconvulsive therapy selectively enhances amyloid β 1-42 in the cerebrospinal fluid of patients with major depression: A prospective pilot study.

Eur Neuropsychopharmacol 2016 12 18;26(12):1877-1884. Epub 2016 Nov 18.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim / Heidelberg University, Mannheim, Germany.

A complex interplay between β-amyloid (Aβ), Alzheimer׳s disease (AD) and major depression disorder (MDD) suggests that patients with MDD have an altered cerebral Aβ metabolism and an increased risk of developing AD. In order to elucidate the relationship between antidepressant treatment and Aβ metabolism in humans, we performed a study on Aβ peptides in the cerebrospinal fluid (CSF) in patients with MDD during electroconvulsive therapy (ECT) as an effective antidepressant treatment. We measured the levels of Aβ, Aβ and of tau proteins in the CSF in 12 patients with MDD before and after a course of ECT. Aβ was significantly elevated after the ECT treatment compared to baseline, whereas no difference was found for other peptides and proteins such as Aβ, Aβ ratio, total tau protein or its phosphorylated form. The most salient finding was, that the increase of Aβ after ECT was found in all patients with clinical response to the treatment, but not in those who did not respond. The number of ECT sessions of each responding patient correlated with the increase of Aβ in the CSF. Our data point towards to a specific antidepressant mechanism which is not based on a general increase of Aβ, but seems to involve merely Aβ, the isoform with highest amyloidogenic potential. We present the first study in humans demonstrating an isolated mobilization of Aβ in the CSF of patients with depression who respond to an ECT treatment.
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http://dx.doi.org/10.1016/j.euroneuro.2016.11.004DOI Listing
December 2016

Heteromultimetallic Complexes with Redox-Active Mesoionic Carbenes: Control of Donor Properties and Redox-Induced Catalysis.

Chemistry 2017 01 14;23(3):576-585. Epub 2016 Dec 14.

Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universität Berlin, Fabeckstraße 34-36, 14195, Berlin, Germany.

Mesoionic carbenes (MICs) are currently hugely popular as ligands, and triazolylidenes are arguably the most prominent classes of such MICs. Mesoionic carbenes with ferrocenyl substituents are presented that can act as metalloligands for the generation of heteromultimetallic iridium(I) and gold(I) complexes. The ferrocenyl substituents allow for reversible oxidation of these heteromultimetallic complexes, and these oxidation steps have a strong influence on the donor properties of the MICs. Tolman electronic parameters (TEP) determined from analysis of the iridium-carbonyl complexes show that the neutral ferrocenyl-MIC ligands are stronger donors than the imidazolylidene based carbenes, the one-electron oxidized ferrocenyl MICs are in the range of the tricyclohexyl phosphines and the two-electron oxidized forms, which are electron-poor, lie in the range of triphenyl phosphines. Taking advantage of the generation of these electron-poor MICs, we show their gold(I) complexes are potent catalysts for the synthesis of oxazolines, with complexes of the oxidized MIC ligands, without any additional additive, outperforming their neutral counterparts by almost a factor of ten. These results thus present the first examples of MIC ligands that are reversibly electronically tunable, and show the potential of the oxidized MIC ligands in types of catalysis where electron-poor ligands are necessary. The potential of MICs for molecular electroactive materials is also shown.
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http://dx.doi.org/10.1002/chem.201604615DOI Listing
January 2017

Decompressive Hemicraniectomy in Malignant Middle Cerebral Artery Infarction: The 'Real World' Beyond Studies.

Eur Neurol 2016 6;76(1-2):48-56. Epub 2016 Jul 6.

Department of Neurology, Universitx00E4;tsmedizin Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Decompressive hemicraniectomy (DHC) is life-saving in patients with malignant middle cerebral artery infarction (MMI), but outcome, perspectives and complications after DHC in daily practice are largely unknown.

Methods: From 2008 until 2014, we extracted patient's characteristics as well as complications from our database for patients with MMI who underwent DHC. Additionally, we analysed medical records from the different rehabilitation steps.

Results: We identified 48 consecutive patients (mean 57 years, 21 male, 41.7% >60 years) with MMI who underwent DHC. The decision for DHC was made on an individual basis, including patients without impaired consciousness or stroke onset >48 h. In-hospital patients achieved only marginal clinical improvement. Seventy-five percent attended an early-rehabilitation, 44% achieved post-stroke rehabilitation and 6% carried on late-stage rehabilitation. In all, 45.5% returned home after rehabilitation. In-hospital mortality was 14.6%, overall mortality was 16.7%. Surviving patients (78.9%) had a modified Rankin Scale of 4-5. Frequent neurologic complications were symptomatic epilepsy and delirium. Following DHC/bone-flap-reimplantation, wound-healing disorders, epidural hematoma and wound infections were major surgery-related complications. Pulmonary infections were frequent in the acute-phase and urinary tract infections were predominant in the late-phase.

Conclusions: DHC is a life-saving technique in patients with MMI, but complications are frequent, were underestimated in randomized clinical trials and may worsen the functional outcome.
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http://dx.doi.org/10.1159/000446564DOI Listing
September 2017

Electronic Structures and Chiroptical Properties of Post-functionalized Helicene Quinones.

Chemistry 2016 05 23;22(21):7152-7. Epub 2016 Apr 23.

Laboratory of Organic Chemistry, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.

The synthesis of redox-active p- and o-quinones 2-phenylamino-4-phenylimino[6]helicene-1-one 1, 2-phenylamino[6]-helicene-1,4-dione 2, and 4-phenyl[6]helicene-1,2-dione 3 in their enantiopure forms by post-functionalization of (P)- and (M)-1,2-dimethoxy[6]helicene is presented. Structural characterization in solution and in the solid state was accomplished by 2D NMR spectroscopy methods and X-ray diffraction analysis, respectively. Interpretation of electrochemical redox data was accompanied by a detailed orbital picture, derived from DFT calculations. The electronic structures of compounds 1-3 were investigated by UV/Vis and electronic circular dichroism (ECD) spectroscopy, complemented by TD-DFT calculations. Quinones 1-3 were chemically reduced to study the EPR signatures of their respective radical anions. DFT methods were used for the atom assignment of the hyperfine coupling constants. The results are discussed within the context of electrochromic chiral switches and molecular recognition.
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http://dx.doi.org/10.1002/chem.201600611DOI Listing
May 2016

Heterobimetallic complexes with redox-active mesoionic carbenes as metalloligands: electrochemical properties, electronic structures and catalysis.

Chem Commun (Camb) 2015 Jul;51(54):10949-52

Institut für Chemie und Biochemie, Freie Universität Berlin, Fabeckstraße 34-36, D-14195, Berlin, Germany.

A mesoionic carbene with a ferrocene backbone is used as a metalloligand to generate the first example of their Fe-Au heterobimetallic complexes. The details of geometric and electronic structures in different redox states and preliminary catalytic results are presented.
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http://dx.doi.org/10.1039/c5cc01578bDOI Listing
July 2015

Type of anesthetic agent, timing, and hyperventilation as covariates in electroconvulsive therapy.

J ECT 2014 Dec;30(4):e39-40

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany Department of Anaesthesiology and Critical Care Medicine, Medical Faculty Mannheim, Heidelberg University, Germany Department of Psychiatry and Psychotherapy, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

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http://dx.doi.org/10.1097/YCT.0000000000000159DOI Listing
December 2014

Advantages and challenges of small animal magnetic resonance imaging as a translational tool.

Neuropsychobiology 2014 23;69(4):187-201. Epub 2014 May 23.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

The utilization of magnetic resonance imaging (MRI) methods in rodent models of psychiatric disorders provides considerable benefits for the identification of disease-associated brain circuits and metabolic changes. In this review, we discuss advantages and challenges of animal MRI and provide an overview of the major structural (voxel-based morphometry and diffusion tensor imaging) and functional approaches [resting-state functional MRI (rs-fMRI), MR spectroscopy (MRS), regional cerebral blood volume measurement and arterial spin labelling] that are applied in animal MRI research. The review mainly focuses on rs-fMRI and MRS. Finally, we take a look at some recent developments and refinements in the field.
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http://dx.doi.org/10.1159/000360859DOI Listing
February 2015

Increased CB2 mRNA and anandamide in human blood after cessation of cannabis abuse.

Naunyn Schmiedebergs Arch Pharmacol 2014 Jul 2;387(7):691-5. Epub 2014 May 2.

Department of Psychiatry and Psychotherapy, University of Cologne, 50924, Cologne, Germany.

In previous studies, long-term cannabis use led to alterations of the endocannabinoid system including an increase in CB1 and/or CB2 receptor messenger RNA (mRNA) in blood cells and an increase in the serum level of the endocannabinoid 2-arachidonoyl glycerol. However, in those studies, cannabis use was stopped only few days before testing or not interrupted at all. Therefore, one cannot decide whether the alterations are due to long-term cannabis abuse or are confounded by acute effects of cannabis. Blood was sampled from donors that had smoked marijuana ≥20 times in their lives but had abstained from cannabis for ≥6 months (high-frequency users, HFU) and from controls (cannabis use ≤5 times lifetime). CB1 and CB2 mRNA was determined in peripheral mononuclear blood cells using the reverse transcriptase polymerase chain reaction. Serum anandamide level was assayed using electrospray tandem mass spectrometry. CB2 mRNA was increased by 45 % in HFU when compared to controls, whereas CB1 mRNA did not differ. The anandamide level in HFU exceeded that in controls by 90 %. Tobacco smoking could be excluded as a confounding factor. In conclusion, marijuana users that had smoked marijuana ≥20 times in their lives and stopped cannabis use at least 6 months before the study show an increase in CB2 receptor mRNA in the blood and in serum anandamide level. These alterations resemble those obtained for marijuana smokers that had stopped cannabis use only few days before testing and may be implicated in the pathogenesis of disorders associated with long-term cannabis use.
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http://dx.doi.org/10.1007/s00210-014-0984-2DOI Listing
July 2014