Recent Submissions

  • Journal Article

    Clot reduction prior to embolectomy: mSAVE as a first-line technique for large clots 

    Psychogios, Marios-Nikos; Tsogkas, Ioannis; Brehm, Alex; Hesse, Amelie; McTaggart, Ryan; Goyal, Mayank; Maier, Ilko; Schnieder, Marlena; Behme, Daniel; Maus, Volker
    PLOS ONE 2019; 14(5): Art. e0216258
    INTRODUCTION: The "Stent retriever Assisted Vacuum-locked Extraction" (SAVE) technique is a promising embolectomy method for intracranial large vessel occlusion (LVO). We report our experience using a modified SAVE (mSAVE) approach for clot reduction prior to embolectomy in acute ischemic stroke patients with large clots. MATERIALS AND METHODS: We retrospectively analyzed 20 consecutive patients undergoing mSAVE in our center due to intracranial LVO. Angiographic data (including first-pass and overall complete reperfusion, defined as an expanded Thrombolysis in Cerebral Infarction (eTICI) score of 3, rate of successful reperfusion (eTICI ≥2c), number of passes, time from groin puncture to reperfusion) and clinical data (favorable outcome at 90 days, defined as modified Rankin Scale (mRS) ≤2) were assessed. RESULTS: First-pass and overall eTICI 3 reperfusion was reached in 13/20 (65%) and 14/20 (70%), respectively. The rate of successful reperfusion (eTICI ≥2c) after one pass was 85% and on final angiogram 90% with an average number of 1.1 ± 0.3 attempts. Eight out of 11 (73%) ICA occlusions were reperfused successfully and 5 (46%) completely after a single pass. Median groin to reperfusion time was 33 minutes (IQR 25-46). A favorable clinical outcome was achieved in 9/20 (45%) patients at discharge and after 90 days, respectively. CONCLUSION: Clot reduction followed by embolectomy (mSAVE) is feasible and may be an important tool in the treatment of large clots.
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  • Journal Article

    The cardiac diagnostic work-up in stroke patients—A subanalysis of the Find-AFRANDOMISED trial 

    Wasser, Katrin; Weber-Krüger, Mark; Jürries, Falko; Liman, Jan; Hamann, Gerhard F.; Kermer, Pawel; Uphaus, Timo; Protsenko, Evgeny; Seegers, Joachim; Mende, Meinhard; et al.
    Gröschel, KlausWachter, Rolf
    PLOS ONE 2019; 14(5): Art. e0216530
    BACKGROUND: The cardiac diagnostic workup of stroke patients, especially the value of echocardiography and enhanced and prolonged Holter-ECG monitoring, is still a matter of debate. We aimed to analyse the impact of pathologies detected by echocardiography and ECG monitoring on therapeutic decisions and prognosis. METHODS: Find-AFRANDOMISED was a prospective multicenter study which randomised 398 acute ischemic stroke patients ≥ 60 years to enhanced and prolonged Holter-ECG monitoring or usual stroke unit care. This substudy compared therapeutic consequences of echocardiography and routine Holter-ECG or enhanced and prolonged Holter-ECG monitoring, respectively, and prognosis of patients with or without pathologic findings in echocardiography or Holter-ECG monitoring. RESULTS: 50.3% received enhanced and prolonged Holter-ECG monitoring and 49.7% routine ECG monitoring. 82.9% underwent transthoracic echocardiography (TTE), 38.9% transesophageal echocardiography (TEE) and 25.6% both procedures. 14/89 TEE pathologies and 1/90 TTE pathology led to a change in therapy, resulting in a number needed to change decision (NNCD) of 12 and 330 (p < 0.001), respectively. In comparison, enhanced and prolonged Holter-ECG monitoring found atrial fibrillation (AF) in 27 of 200 patients, and routine ECG monitoring in twelve of 198 patients, leading to therapeutic changes in all patients (NNCD 8 and 17, respectively, p < 0.001). CONCLUSIONS: Most changes in therapeutic decisions were triggered by enhanced and prolonged Holter-ECG monitoring, which should therefore play a more prominent role in future guidelines. Echocardiography identifies a patient group at high cardiovascular risk, but rarely result in therapeutic changes. Whether this patient group requires further cardiovascular workup remains unknown. This should be further investigated by interdisciplinary neurocardiologic teams and in appropriate future trials.
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  • Journal Article

    “I can’t get it into my head that I have cancer…” - A qualitative interview study on needs of patients with lung cancer 

    Stanze, Henrikje; Schneider, Nils; Nauck, Friedemann; Marx, Gabriella
    PLOS ONE 2019; 14(5): Art. e0216778
    BACKGROUND: Caring for patients with advanced lung cancer is of high relevance in different clinical settings. Lung cancer is among the most common causes of death from malignant neoplasms worldwide; with increasing prevalence and mortality. AIM: To get a better understanding of individual patients' needs, exploring the experiences and meaning of living with advanced lung cancer at the end of life, and to develop strategies for improving patient-centred care in Germany. DESIGN: Qualitative explorative interview study with patients, using grounded theory. SETTING/PARTICIPANTS: A sample of 17 adults living with advanced lung cancer in Lower Saxony/Germany was recruited in two university hospitals. Patients were asked to tell of their experiences of living with advanced lung cancer. The emphasis of this study was the period of palliative tumour therapy. RESULTS: The main phenomenon of living with advanced lung cancer is the feeling of having to redefine one's own existence, such as social roles within and outside the family. The diagnosis trigger powerlessness, which can lead to information passivity, followed by acceptance of aggressive tumour treatment. Patients perceive a high degree of psychological and social stress, without being able to express this. There is a lack of regular appropriate psychosocial care accompanying chemotherapy. Patients ascribe their physical suffering to the side effects of tumour treatment, which may trigger a desire to die. Finally, patients tend to hide their individual needs, even when asked. CONCLUSIONS: Regarding the patients' needs, greater emphasis must be placed on psychosocial care as part of the biopsychosocial model to adequately consider the patients' concerns. Assessments can be helpful to enhance communication at an early stage across all professions into the multi-professional therapy.
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  • Journal Article

    Computational identification of tissue-specific transcription factor cooperation in ten cattle tissues 

    Steuernagel, Lukas; Meckbach, Cornelia; Heinrich, Felix; Zeidler, Sebastian; Schmitt, Armin O.; Gültas, Mehmet
    PLOS ONE 2019; 14(5): Art. e0216475
    Transcription factors (TFs) are a special class of DNA-binding proteins that orchestrate gene transcription by recruiting other TFs, co-activators or co-repressors. Their combinatorial interplay in higher organisms maintains homeostasis and governs cell identity by finely controlling and regulating tissue-specific gene expression. Despite the rich literature on the importance of cooperative TFs for deciphering the mechanisms of individual regulatory programs that control tissue specificity in several organisms such as human, mouse, or Drosophila melanogaster, to date, there is still need for a comprehensive study to detect specific TF cooperations in regulatory processes of cattle tissues. To address the needs of knowledge about specific combinatorial gene regulation in cattle tissues, we made use of three publicly available RNA-seq datasets and obtained tissue-specific gene (TSG) sets for ten tissues (heart, lung, liver, kidney, duodenum, muscle tissue, adipose tissue, colon, spleen and testis). By analyzing these TSG-sets, tissue-specific TF cooperations of each tissue have been identified. The results reveal that similar to the combinatorial regulatory events of model organisms, TFs change their partners depending on their biological functions in different tissues. Particularly with regard to preferential partner choice of the transcription factors STAT3 and NR2C2, this phenomenon has been highlighted with their five different specific cooperation partners in multiple tissues. The information about cooperative TFs could be promising: i) to understand the molecular mechanisms of regulating processes; and ii) to extend the existing knowledge on the importance of single TFs in cattle tissues.
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  • Journal Article

    Higher Level of Mismatch in APOEε4 Carriers for Amyloid-Beta Peptide Alzheimer’s Disease Biomarkers in Cerebrospinal Fluid 

    Vogelgsang, Jonathan; Vukovich, Ruth; Wedekind, Dirk; Wiltfang, Jens
    ASN Neuro 2019; 11 p.1-8
    Cerebrospinal fluid (CSF) biomarkers are widely used in the diagnosis of dementia. Even though there is a causal correlation between apolipoprotein E ( APOE) genotype and amyloid-beta (Aβ), the determination of APOE is currently not supported by national or international guidelines. We compared parallel measured CSF biomarkers of two independent laboratories from 126 patients who underwent clinical dementia diagnostics regarding the APOE genotype. APOE ε4 reduces Aβ1-42 (Aβ42) and Aβ42 to Aβ 1-40 ratio (Aβ42/40) but not total Tau or phospho-181 Tau CSF levels. Higher discordance rates were observed for Aβ42 and subsequently for Aβ42/40 in APOE ε4 carriers compared with noncarriers, and the correlation between the two laboratories was significantly lower for Aβ42 in APOE ε4 positive patients compared with patients without APOE ε4. These observations demonstrate that the evaluation of CSF Aβ biomarkers needs to be interpreted carefully in the clinical context. Different immunoassays, disparate cutoff values, and APOE should be respected.
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  • Journal Article

    Rapamycin administration is not a valid therapeutic strategy for every case of mitochondrial disease 

    Barriocanal-Casado, Eliana; Hidalgo-Gutiérrez, Agustín; Raimundo, Nuno; González-García, Pilar; Acuña-Castroviejo, Darío; Escames, Germaine; López, Luis C.
    EBioMedicine 2019; 42 p.511-523
    BACKGROUND: The vast majority of mitochondrial disorders have limited the clinical management to palliative care. Rapamycin has emerged as a potential therapeutic drug for mitochondrial diseases since it has shown therapeutic benefits in a few mouse models of mitochondrial disorders. However, the underlying therapeutic mechanism is unclear, the minimal effective dose needs to be defined and whether this therapy can be generally used is unknown. METHODS: We have evaluated whether low and high doses of rapamycin administration may result in therapeutic effects in a mouse model (Coq9R239X) of mitochondrial encephalopathy due to CoQ deficiency. The evaluation involved phenotypic, molecular, image (histopathology and MRI), metabolomics, transcriptomics and bioenergetics analyses. FINDINGS: Low dose of rapamycin induces metabolic changes in liver and transcriptomics modifications in midbrain. The high dose of rapamycin induces further changes in the transcriptomics profile in midbrain due to the general inhibition of mTORC1. However, neither low nor high dose of rapamycin were able to improve the mitochondrial bioenergetics, the brain injuries and the phenotypic characteristics of Coq9R239X mice, resulting in the lack of efficacy for increasing the survival. INTERPRETATION: These results may be due to the lack of microgliosis-derived neuroinflammation, the limitation to induce autophagy, or the need of a functional CoQ-junction. Therefore, the translation of rapamycin therapy into the clinic for patients with mitochondrial disorders requires, at least, the consideration of the particularities of each mitochondrial disease. FUND: Supported by the grants from "Fundación Isabel Gemio - Federación Española de Enfermedades Neuromusculares - Federación FEDER" (TSR-1), the NIH (P01HD080642) and the ERC (Stg-337327).
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  • Journal Article

    Editorial: Mitochondrial Communication in Physiology, Disease and Aging 

    Raimundo, Nuno; Krisko, Anita
    Frontiers in Cell and Developmental Biology 2019; 7: Art. 54
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  • Journal Article

    Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis 

    Fernandez-Mosquera, Lorena; Yambire, King Faisal; Couto, Renata; Pereyra, Leonardo; Pabis, Kamil; Ponsford, Amy H.; Diogo, Cátia V.; Stagi, Massimiliano; Milosevic, Ira; Raimundo, Nuno
    Autophagy(27) p.1-20
    Mitochondria are key organelles for cellular metabolism, and regulate several processes including cell death and macroautophagy/autophagy. Here, we show that mitochondrial respiratory chain (RC) deficiency deactivates AMP-activated protein kinase (AMPK, a key regulator of energy homeostasis) signaling in tissue and in cultured cells. The deactivation of AMPK in RC-deficiency is due to increased expression of the AMPK-inhibiting protein FLCN (folliculin). AMPK is found to be necessary for basal lysosomal function, and AMPK deactivation in RC-deficiency inhibits lysosomal function by decreasing the activity of the lysosomal Ca2+ channel MCOLN1 (mucolipin 1). MCOLN1 is regulated by phosphoinositide kinase PIKFYVE and its product PtdIns(3,5)P2, which is also decreased in RC-deficiency. Notably, reactivation of AMPK, in a PIKFYVE-dependent manner, or of MCOLN1 in RC-deficient cells, restores lysosomal hydrolytic capacity. Building on these data and the literature, we propose that downregulation of the AMPK-PIKFYVE-PtdIns(3,5)P2-MCOLN1 pathway causes lysosomal Ca2+ accumulation and impaired lysosomal catabolism. Besides unveiling a novel role of AMPK in lysosomal function, this study points to the mechanism that links mitochondrial malfunction to impaired lysosomal catabolism, underscoring the importance of AMPK and the complexity of organelle cross-talk in the regulation of cellular homeostasis. Abbreviation: ΔΨm: mitochondrial transmembrane potential; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATP: adenosine triphosphate; ATP6V0A1: ATPase, H+ transporting, lysosomal, V0 subbunit A1; ATP6V1A: ATPase, H+ transporting, lysosomal, V0 subbunit A; BSA: bovine serum albumin; CCCP: carbonyl cyanide-m-chlorophenylhydrazone; CREB1: cAMP response element binding protein 1; CTSD: cathepsin D; CTSF: cathepsin F; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; EBSS: Earl's balanced salt solution; ER: endoplasmic reticulum; FBS: fetal bovine serum; FCCP: carbonyl cyanide-p-trifluoromethoxyphenolhydrazone; GFP: green fluorescent protein; GPN: glycyl-L-phenylalanine 2-naphthylamide; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryonic fibroblast; MITF: melanocyte inducing transcription factor; ML1N*2-GFP: probe used to detect PtdIns(3,5)P2 based on the transmembrane domain of MCOLN1; MTORC1: mechanistic target of rapamycin kinase complex 1; NDUFS4: NADH:ubiquinone oxidoreductase subunit S4; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; pcDNA: plasmid cytomegalovirus promoter DNA; PCR: polymerase chain reaction; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; P/S: penicillin-streptomycin; PVDF: polyvinylidene fluoride; qPCR: quantitative real time polymerase chain reaction; RFP: red fluorescent protein; RNA: ribonucleic acid; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; shRNA: short hairpin RNA; siRNA: small interfering RNA; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TMRM: tetramethylrhodamine, methyl ester, perchlorate; ULK1: unc-51 like autophagy activating kinase 1; ULK2: unc-51 like autophagy activating kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; v-ATPase: vacuolar-type H+-translocating ATPase; WT: wild-type.
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  • Journal Article

    Semi‐parametric analysis of overdispersed count and metric data with varying follow‐up times: Asymptotic theory and small sample approximations 

    Konietschke, Frank; Friede, Tim; Pauly, Markus
    Biometrical Journal 2019; 61(3) p.616-629
    Count data are common endpoints in clinical trials, for example magnetic resonance imaging lesion counts in multiple sclerosis. They often exhibit high levels of overdispersion, that is variances are larger than the means. Inference is regularly based on negative binomial regression along with maximum-likelihood estimators. Although this approach can account for heterogeneity it postulates a common overdispersion parameter across groups. Such parametric assumptions are usually difficult to verify, especially in small trials. Therefore, novel procedures that are based on asymptotic results for newly developed rate and variance estimators are proposed in a general framework. Moreover, in case of small samples the procedures are carried out using permutation techniques. Here, the usual assumption of exchangeability under the null hypothesis is not met due to varying follow-up times and unequal overdispersion parameters. This problem is solved by the use of studentized permutations leading to valid inference methods for situations with (i) varying follow-up times, (ii) different overdispersion parameters, and (iii) small sample sizes.
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  • Journal Article

    Near physiological spectral selectivity of cochlear optogenetics 

    Dieter, Alexander; Duque-Afonso, Carlos J.; Rankovic, Vladan; Jeschke, Marcus; Moser, Tobias
    Nature Communications 2019; 10(1): Art. 1962
    Cochlear implants (CIs) electrically stimulate spiral ganglion neurons (SGNs) and partially restore hearing to half a million CI users. However, wide current spread from intracochlear electrodes limits spatial selectivity (i.e. spectral resolution) of electrical CIs. Optogenetic stimulation might become an alternative, since light can be confined in space, promising artificial sound encoding with increased spectral selectivity. Here we compare spectral selectivity of optogenetic, electric, and acoustic stimulation by multi-channel recordings in the inferior colliculus (IC) of gerbils. When projecting light onto tonotopically distinct SGNs, we observe corresponding tonotopically ordered IC activity. An activity-based comparison reveals that spectral selectivity of optogenetic stimulation is indistinguishable from acoustic stimulation for modest intensities. Moreover, optogenetic stimulation outperforms bipolar electric stimulation at medium and high intensities and monopolar electric stimulation at all intensities. In conclusion, we demonstrate better spectral selectivity of optogenetic over electric SGN stimulation, suggesting the potential for improved hearing restoration by optical CIs.
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  • Journal Article

    Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer 

    Weber-Lassalle, Nana; Borde, Julika; Weber-Lassalle, Konstantin; Horváth, Judit; Niederacher, Dieter; Arnold, Norbert; Kaulfuß, Silke; Ernst, Corinna; Paul, Victoria G.; Honisch, Ellen; et al.
    Klaschik, KristinaVolk, Alexander E.Kubisch, ChristianRapp, SteffenLichey, NadineAltmüller, JanineLepkes, LouisaPohl-Rescigno, EstherThiele, HolgerNürnberg, PeterLarsen, MirjamRichters, LisaRhiem, KerstinWappenschmidt, BarbaraEngel, ChristophMeindl, AlfonsSchmutzler, Rita K.Hahnen, EricHauke, Jan
    Breast Cancer Research 2019; 21(1): Art. 55
    BACKGROUND: The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). METHODS: A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs). RESULTS: We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17-9.04; P < 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC. CONCLUSIONS: Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.
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  • Journal Article

    Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents 

    Luo, Qiang; Chen, Qiang; Wang, Wenjia; Desrivières, Sylvane; Quinlan, Erin Burke; Jia, Tianye; Macare, Christine; Robert, Gabriel H.; Cui, Jing; Guedj, Mickaël; et al.
    Palaniyappan, LenaKherif, FerathBanaschewski, TobiasBokde, Arun L. W.Büchel, ChristianFlor, HertaFrouin, VincentGaravan, HughGowland, PennyHeinz, AndreasIttermann, BerndMartinot, Jean-LucArtiges, EricPaillère-Martinot, Marie-LaureNees, FraukeOrfanos, Dimitri PapadopoulosPoustka, LuiseFröhner, Juliane H.Smolka, Michael N.Walter, HenrikWhelan, RobertCallicott, Joseph H.Mattay, Venkata S.Pausova, ZdenkaDartigues, Jean-FrançoisTzourio, ChristopheCrivello, FabriceBerman, Karen F.Li, FeiPaus, TomášWeinberger, Daniel R.Murray, Robin M.Schumann, GunterFeng, Jianfeng
    JAMA Psychiatry 2019; 76(4)
    Importance: Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology. Objective: To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations. Design, Setting, and Participants: Voxelwise genome-wide association study in a cohort of healthy adolescents aged 14 years and validation of the findings using 4 independent samples across the life span with allele-specific expression analysis of top hits. Group comparison of the identified gene-brain association among patients with schizophrenia, unaffected siblings, and healthy control individuals. This was a population-based, multicenter study combined with a clinical sample that included participants from the IMAGEN cohort, Saguenay Youth Study, Three-City Study, and Lieber Institute for Brain Development sample cohorts and UK biobank who were assessed for both brain imaging and genetic sequencing. Clinical samples included patients with schizophrenia and unaffected siblings of patients from the Lieber Institute for Brain Development study. Data were analyzed between October 2015 and April 2018. Main Outcomes and Measures: Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip. Results: The discovery sample included 1721 adolescents (873 girls [50.7%]), with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of 8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the life span. A nonsynonymous genetic variant (minor T allele of rs13107325 in SLC39A8, a gene implicated in schizophrenia) was associated with greater gray matter volume of the putamen (variance explained of 4.21% in the left hemisphere; 8.66; 95% CI, 6.59-10.81; P = 5.35 × 10-18; and 4.44% in the right hemisphere; t = 8.90; 95% CI, 6.75-11.19; P = 6.80 × 10-19) and also with a lower gene expression of SLC39A8 specifically in the putamen (t127 = -3.87; P = 1.70 × 10-4). The identified association was validated in samples across the life span but was significantly weakened in both patients with schizophrenia (z = -3.05; P = .002; n = 157) and unaffected siblings (z = -2.08; P = .04; n = 149). Conclusions and Relevance: Our results show that a missense mutation in gene SLC39A8 is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. These results may suggest a role for aberrant ion transport in the etiology of psychosis and provide a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation.
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  • Journal Article

    Medial prefrontal cortex supports perceptual memory 

    Schwiedrzik, Caspar M.; Sudmann, Sandrin S.; Thesen, Thomas; Wang, Xiuyuan; Groppe, David M.; Mégevand, Pierre; Doyle, Werner; Mehta, Ashesh D.; Devinsky, Orrin; Melloni, Lucia
    Current Biology 2018; 28(18) p.R1094-R1095
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  • Journal Article

    Nanomachinery Organizing Release at Neuronal and Ribbon Synapses 

    Chakrabarti; Wichmann
    International Journal of Molecular Sciences 2019; 20(9): Art. 2147
    A critical aim in neuroscience is to obtain a comprehensive view of how regulated neurotransmission is achieved. Our current understanding of synapses relies mainly on data from electrophysiological recordings, imaging, and molecular biology. Based on these methodologies, proteins involved in a synaptic vesicle (SV) formation, mobility, and fusion at the active zone (AZ) membrane have been identified. In the last decade, electron tomography (ET) combined with a rapid freezing immobilization of neuronal samples opened a window for understanding the structural machinery with the highest spatial resolution in situ. ET provides significant insights into the molecular architecture of the AZ and the organelles within the presynaptic nerve terminal. The specialized sensory ribbon synapses exhibit a distinct architecture from neuronal synapses due to the presence of the electron-dense synaptic ribbon. However, both synapse types share the filamentous structures, also commonly termed as tethers that are proposed to contribute to different steps of SV recruitment and exocytosis. In this review, we discuss the emerging views on the role of filamentous structures in SV exocytosis gained from ultrastructural studies of excitatory, mainly central neuronal compared to ribbon-type synapses with a focus on inner hair cell (IHC) ribbon synapses. Moreover, we will speculate on the molecular entities that may be involved in filament formation and hence play a crucial role in the SV cycle.
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  • Journal Article

    Prolonged Cannabidiol Treatment Lacks on Detrimental Effects on Memory, Motor Performance and Anxiety in C57BL/6J Mice 

    Schleicher, Eva M.; Ott, Frederik W.; Müller, Melanie; Silcher, Barbara; Sichler, Marius E.; Löw, Maximilian J.; Wagner, Jannek M.; Bouter, Yvonne
    Frontiers in Behavioral Neuroscience 2019; 13: Art. 94
    The Cannabis plant contains more than 100 currently known phytocannabinoids. Regarding the rising consumption of the non-psychotropic phytocannabinoid cannabidiol (CBD) in people’s everyday life (e.g., beauty products, food and beverages), the importance of studies on the influence of CBD on healthy humans and rodents is evident. Therefore, the behavioral profile of CBD was investigated with a battery of behavioral tests, including motor, anxiety, and memory tests after prolonged CBD treatment. Adult C57Bl/6J wildtype (WT) mice were daily intraperitoneally injected with 20 mg/kg CBD for 6 weeks starting at two different points of ages (3 months and 5 months) to compare the influence of prolonged CBD treatment with a washout period (former group) to the effects of long term CBD treatment (current group). Our results show that CBD treatment does not influence motor performance on an accelerating Rotarod test, while it also results in a lower locomotor activity in the open field (OF). No influence of CBD on spatial learning and long term memory in the Morris Water Maze (MWM) was observed. Memory in the Novel Object Recognition test (NORT) was unaffected by CBD treatment. Two different anxiety tests revealed that CBD does not affect anxiety behavior in the Dark-Light Box (DLB) and OF test. Although, anxiety is altered by current CBD treatment in the Elevated Plus Maze (EPM). Moreover, CBDtreated C57Bl/6J mice showed an unaltered acoustic startle response (ASR) compared to vehicle-treated mice. However, current CBD treatment impairs prepulse inhibition (PPI), a test to analyze sensorimotor gating. Furthermore, prolonged CBD treatment did not affect the hippocampal neuron number. Our results demonstrate that prolonged CBD treatment has no negative effect on the behavior of adult C57Bl/6J mice.
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  • Journal Article

    Amygdalar reactivity is associated with prefrontal cortical thickness in a large population-based sample of adolescents 

    Albaugh, Matthew D.; Hudziak, James. J.; Orr, Catherine; Spechler, Philip A.; Chaarani, Bader; Mackey, Scott; Lepage, Claude; Fonov, Vladimir; Rioux, Pierre; Evans, Alan C.; et al.
    Banaschewski, TobiasBokde, Arun L. W.Bromberg, UliBüchel, ChristianQuinlan, Erin BurkeDesrivières, SylvaneFlor, HertaGrigis, AntoineGowland, PennyHeinz, AndreasIttermann, BerndMartinot, Jean-LucMartinot, Marie-Laure PaillèreNees, FraukeOrfanos, Dimitri PapadopoulosPaus, TomášPoustka, LuiseMillenet, SabinaFröhner, Juliane H.Smolka, Michael N.Walter, HenrikWhelan, RobertSchumann, GunterPotter, Alexandra S.Garavan, Hugh
    PLOS ONE 2019; 14(5): Art. e0216152
    In structural neuroimaging studies, reduced cerebral cortical thickness in orbital and ventromedial prefrontal regions is frequently interpreted as reflecting an impaired ability to downregulate neuronal activity in the amygdalae. Unfortunately, little research has been conducted in order to test this conjecture. We examine the extent to which amygdalar reactivity is associated with cortical thickness in a population-based sample of adolescents. Data were obtained from the IMAGEN study, which includes 2,223 adolescents. While undergoing functional neuroimaging, participants passively viewed video clips of a face that started from a neutral expression and progressively turned angry, or, instead, turned to a second neutral expression. Left and right amygdala ROIs were used to extract mean BOLD signal change for the angry minus neutral face contrast for all subjects. T1-weighted images were processed through the CIVET pipeline (version 2.1.0). In variable-centered analyses, local cortical thickness was regressed against amygdalar reactivity using first and second-order linear models. In a follow-up person-centered analysis, we defined a "high reactive" group of participants based on mean amygdalar BOLD signal change for the angry minus neutral face contrast. Between-group differences in cortical thickness were examined ("high reactive" versus all other participants). A significant association was revealed between the continuous measure of amygdalar reactivity and bilateral ventromedial prefrontal cortical thickness in a second-order linear model (p < 0.05, corrected). The "high reactive" group, in comparison to all other participants, possessed reduced cortical thickness in bilateral orbital and ventromedial prefrontal cortices, bilateral anterior temporal cortices, left caudal middle temporal gyrus, and the left inferior and middle frontal gyri (p < 0.05, corrected). Results are consistent with non-human primate studies, and provide empirical support for an association between reduced prefrontal cortical thickness and amygdalar reactivity. Future research will likely benefit from investigating the degree to which psychopathology qualifies relations between prefrontal cortical structure and amygdalar reactivity.
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  • Journal Article

    Subparaneural injection in popliteal sciatic nerve blocks evaluated by MRI 

    Büttner, Benedikt; Schwarz, Alexander; Mewes, Caspar; Kristof, Katalin; Hinz, José; Quintel, Michael; Mansur, Ashham; Bergmann, Ingo
    Open Medicine 2019; 14(1) p.346-353
    Intraneural injection of a local anesthetic can damage the nerve, yet it occurs frequently during distal sciatic block with no neurological sequelae. This has led to a controversy about the optimal needle tip placement that results from the particular anatomy of the sciatic nerve with its paraneural sheath. The study population included patients undergoing lower extremity surgery under popliteal sciatic nerve block. Ultrasound-guidance was used to position the needle tip subparaneurally and to monitor the injection of the local anesthetic. Sonography and magnetic resonance imaging were used to assess the extent of the subparaneural injection. Twenty-two patients participated. The median sciatic cross-sectional area increased from 57.8 mm2 pre-block to 110.8 mm2 immediately post-block. An intraneural injection according to the current definition was seen in 21 patients. Two patients had sonographic evidence of an intrafascicular injection, which was confirmed by MRI in one patient (the other patient refused further examinations). No patient reported any neurological symptoms. A subparaneural injection in the popliteal segment of the distal sciatic nerve is actually rarely intraneural, i.e. intrafascicular. This may explain the discrepancy between the conventional sonographic evidence of an intraneural injection and the lack of neurological sequelae.
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  • Journal Article

    Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved 

    Vasili, Eftychia; Dominguez-Meijide, Antonio; Outeiro, Tiago Fleming
    Frontiers in Molecular Neuroscience 2019; 12: Art. 107
    Alzheimer's disease (AD) and Parkinson's disease (PD) are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn) and tau, respectively. The coexistence of aSyn and tau aggregates suggests a strong overlap between tauopathies and synucleinopathies. Interestingly, misfolded forms of aSyn and tau can propagate from cell to cell, and throughout the brain, thereby templating the misfolding of native forms of the proteins. The exact mechanisms involved in the propagation of the two proteins show similarities, and are reminiscent of the spreading characteristic of prion diseases. Recently, several models were developed to study the spreading of aSyn and tau. Here, we discuss the mechanisms involved, the similarities and differences between the spreading of the two proteins and that of the prion protein, and the different cell and animal models used for studying these processes. Ultimately, a deeper understanding of the molecular mechanisms involved may lead to the identification of novel targets for therapeutic intervention in a variety of devastating neurodegenerative diseases.
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  • Journal Article

    How Uncertainty Influences Lay People’s Attitudes and Risk Perceptions Concerning Predictive Genetic Testing and Risk Communication 

    Wöhlke, Sabine; Schaper, Manuel; Schicktanz, Silke
    Frontiers in Genetics 2019; 10: Art. 380
    The interpretation of genetic information in clinical settings raises moral issues about adequate risk communication and individual responsibility about one’s health behavior. However, it is not well-known what role numeric probabilities and/or the conception of disease and genetics play in the lay understanding of predictive genetic diagnostics. This is an important question because lay understanding of genetic risk information might have particular implications for self-responsibility of the patients. Aim: Analysis of lay attitudes and risk perceptions of German lay people on genetic testing with a special focus on how they deal with the numerical information. Methods: We conducted and analyzed seven focus group discussions (FG) with lay people (n = 43). Results: Our participants showed a positive attitude toward predictive genetic testing. We identified four main topics: (1) Anumeric risk instead of statistical information; (2) Treatment options as a factor for risk evaluation; (3) Epistemic and aleatory uncertainty as moral criticism; (4) Ambivalence as a sign of uncertainty. Conclusion: For lay people, risk information, including the statistical numeric part, is perceived as highly normatively charged, often as an emotionally significant threat. It seems necessary to provide lay people with a deeper understanding of risk information and of the limitations of genetic knowledge with respect to one’s own health responsibility.
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  • Journal Article

    Optogenetic Hyperpolarization of Cardiomyocytes Terminates Ventricular Arrhythmia 

    Funken, Maximilian; Malan, Daniela; Sasse, Philipp; Bruegmann, Tobias
    Frontiers in Physiology 2019; 10: Art. 498
    Cardiac defibrillation to terminate lethal ventricular arrhythmia (VA) is currently performed by applying high energy electrical shocks. In cardiac tissue, electrical shocks induce simultaneously de- and hyperpolarized areas and only depolarized areas are considered to be responsible for VA termination. Because electrical shocks do not allow proper control over spatial extent and level of membrane potential changes, the effects of hyperpolarization have not been explored in the intact heart. In contrast, optogenetic methods allow cell type-selective induction of de- and hyperpolarization with unprecedented temporal and spatial control. To investigate effects of cardiomyocyte hyperpolarization on VA termination, we generated a mouse line with cardiomyocyte-specific expression of the light-driven proton pump ArchT. Isolated cardiomyocytes showed light-induced outward currents and hyperpolarization. Free-running VA were evoked by electrical stimulation of explanted hearts perfused with low K+ and the KATP channel opener Pinacidil. Optogenetic hyperpolarization was induced by epicardial illumination, which terminated VA with an average efficacy of ∼55%. This value was significantly higher compared to control hearts without illumination or ArchT expression (p = 0.0007). Intracellular recordings with sharp electrodes within the intact heart revealed hyperpolarization and faster action potential upstroke upon illumination, which should fasten conduction. However, conduction speed was lower during illumination suggesting enhanced electrical sink by hyperpolarization underlying VA termination. Thus, selective hyperpolarization in cardiomyocytes is able to terminate VA with a completely new mechanism of increased electrical sink. These novel insights could improve our mechanistic understanding and treatment strategies of VA termination.
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