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Hintergrund und Ziel
Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, ländlichen Regionen zu gewährleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur.
Methoden
Die Kommission „Telemedizinische Schlaganfallversorgung“ der Deutschen Schlaganfall-Gesellschaft führte eine Umfragestudie in allen Schlaganfall-Netzwerken durch.
Ergebnisse
In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1–3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4–17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung für 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319–2758) durchgeführt. Die Thrombolyserate betrug 14,1 % (95 %-Konfidenzintervall 13,6–14,7 %), eine Verlegung zur Thrombektomie wurde bei 7,9 % (95 %-Konfidenzintervall 7,5–8,4 %) der ischämischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Vergütungssystem für die Zentrumsleistungen in nur drei Bundesländern.
Diskussion
Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer flächendeckenden Schlaganfallversorgung bei. Eine netzwerkübergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualitätssicherungsdaten haben das Potenzial diese Versorgungsstruktur zukünftig weiter zu stärken.
Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice
(2014)
The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.
Chromium dioxide CrO\(_2\) belongs to a class of materials called ferromagnetic half-metals, whose peculiar aspect is that they act as a metal in one spin orientation and as a semiconductor or insulator in the opposite one. Despite numerous experimental and theoretical studies motivated by technologically important applications of this material in spintronics, its fundamental properties such as momentumresolved electron dispersions and the Fermi surface have so far remained experimentally inaccessible because of metastability of its surface, which instantly reduces to amorphous Cr\(_2\)O\(_3\). In this work, we demonstrate that direct access to the native electronic structure of CrO\(_2\) can be achieved with soft-x-ray angle-resolved photoemission spectroscopy whose large probing depth penetrates through the Cr\(_2\)O\(_3\) layer. For the first time, the electronic dispersions and Fermi surface of CrO\(_2\) are measured, which are fundamental prerequisites to solve the long debate on the nature of electronic correlations in this material. Since density functional theory augmented by a relatively weak local Coulomb repulsion gives an exhaustive description of our spectroscopic data, we rule out strong-coupling theories of CrO\(_2\). Crucial for the correct interpretation of our experimental data in terms of the valence-band dispersions is the understanding of a nontrivial spectral response of CrO\(_2\) caused by interference effects in the photoemission process originating from the nonsymmorphic space group of the rutile crystal structure of CrO\(_2\).
Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans
(2016)
In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies.
MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
Background
Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) by anti‐Dsg3 IgG inducing erosions in the mucosa; and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3.
Objectives
To characterize the Ca\(^{2+}\) flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles.
Methods
Immunoprecipitation, Ca\(^{2+}\) flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used.
Results
PV IgG and PF IgG, but neither Dsg3‐specific monoclonal antibody (AK23) nor mPV IgG, caused Ca\(^{2+}\) influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (PLC) – was activated by PV IgG and PF IgG but not AK23 or mPV IgG. PLC releases inositol 1,4,5‐trisphosphate (IP3) causing IP3 receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ release‐activated channels (CRAC)‐mediated Ca\(^{2+}\) influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca\(^{2+}\) influx; ameliorated alterations of Dsg1 and Dsg3 localization, and reorganization of keratin and actin filaments; and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV IgG‐induced blister formation and redistribution of Dsg1 and Dsg3 in human skin ex vivo.
Conclusions
Ca2+‐mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca\(^{2+}\) signalling may be a promising approach to treat epidermal manifestations of pemphigus.
Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.
Pharmacobehavioral studies in experimental animals, and imaging studies in humans, indicate that serotonergic transmission in the amygdala plays a key role in emotional processing, especially for anxiety-related stimuli. The lateral and basolateral amygdaloid nuclei receive a dense serotonergic innervation in all species studied to date. We investigated interrelations between serotonergic afferents and neuropeptide Y (NPY)-producing neurons, which are a subpopulation of inhibitory interneurons in the rat lateral and basolateral nuclei with particularly strong anxiolytic properties. Dual light microscopic immunolabeling showed numerous appositions of serotonergic afferents on NPY-immunoreactive somata. Using electron microscopy, direct membrane appositions and synaptic contacts between serotonin-containing axon terminals and NPY-immunoreactive cellular profiles were unequivocally established. Double in situ hybridization documented that more than 50 %, and about 30–40 % of NPY mRNA-producing neurons, co-expressed inhibitory 5-HT1A and excitatory 5-HT2C mRNA receptor subtype mRNA, respectively, in both nuclei with no gender differences. Triple in situ hybridization showed that individual NPY mRNA-producing interneurons co-express both 5-HT1A and 5-HT2C mRNAs. Co-expression of NPY and 5-HT3 mRNA was not observed. The results demonstrate that serotonergic afferents provide substantial innervation of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Studies of serotonin receptor subtype co-expression indicate a differential impact of the serotonergic innervation on this small, but important, population of anxiolytic interneurons, and provide the basis for future studies of the circuitry underlying serotonergic modulation of emotional stimulus processing in the amygdala.
The treatment of Parkinson's disease by transplantation of dopaminergic (DA) neurons from human embryonic mesencephalic tissue is a promising approach. However, the origin of these cells causes major problems: availability and standardization of the graft. Therefore, the generation of unlimited numbers of DA neurons from various types of stem or progenitor cells has been brought into focus. A source for DA neurons might be conditionally immortalized progenitor cells. The temperature-sensitive immortalized cell line CSM14.1 derived from the mesencephalon of an embryonic rat has been used successfully for transplantation experiments. This cell line was analyzed by unbiased stereology of cell type specific marker proteins and 2D-gel electrophoresis followed by mass spectrometry to characterize the differentially expressed proteome. Undifferentiated CSM14.1 cells only expressed the stem cell marker nestin, whereas differentiated cells expressed GFAP or NeuN and tyrosine hydroxylase. An increase of the latter cells during differentiation could be shown. By using proteomics an explanation on the protein level was found for the observed changes in cell morphology during differentiation, when CSM14.1 cells possessed the morphology of multipolar neurons. The results obtained in this study confirm the suitability of CSM14.1 cells as an in vitro model for the study of neuronal and dopaminergic differentiation in rats.
Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.
Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.
The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.
Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.
The development of controlled biodegradable materials is of fundamental importance in immunodrug delivery to spatiotemporally controlled immune stimulation but avoid systemic inflammatory side effects. Based on this, polycarbonate nanogels are developed as degradable micellar carriers for transient immunoactivation of lymph nodes. An imidazoquinoline‐type TLR7/8 agonist is covalently conjugated via reactive ester chemistry to these nanocarriers. The nanogels not only provide access to complete disintegration by the hydrolysable polymer backbone, but also demonstrate a gradual disintegration within several days at physiological conditions (PBS, pH 6.4–7.4, 37 °C). These intrinsic properties limit the lifetime of the carriers but their payload can still be successfully leveraged for immunological studies in vitro on primary immune cells as well as in vivo. For the latter, a spatiotemporal control of immune cell activation in the draining lymph node is found after subcutaneous injection. Overall, these features render polycarbonate nanogels a promising delivery system for transient activation of the immune system in lymph nodes and may consequently become very attractive for further development toward vaccination or cancer immunotherapy. Due to the intrinsic biodegradability combined with the high chemical control during the manufacturing process, these polycarbonate‐based nanogels may also be of great importance for clinical translation.
Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2\(^{-/-}\)) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph\(^{+/-}\)) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.