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Background: The surgical treatment of giant olfactory groove meningiomas (OGMs) with marked perilesional brain oedema is still a surgical challenge. After tumour resection, increase of brain oedema may occur causing dramatic neurological deterioration and even death of the patient. The objective of this paper is to describe surgical features of a two-step staged resection of these tumours performed to counter increase of postoperative brain oedema.
Methods: This two-step staged resection procedure was carried out in a consecutive series of 19 patients harbouring giant OGMs. As first step, a bifrontal craniectomy was performed followed by a right-sided interhemispherical approach. About 80% of the tumour mass was resected leaving behind a shell-shaped tumour remnant. In the second step, carried out after the patients’ recovery from the first surgery and decline of oedema, the remaining part of the tumour was removed completely followed by duro- and cranioplasty.
Results: Ten patients recovered quickly from first surgery and the second operation was performed after a mean of 12.4 days. In eight patients, the second operation was carried out later between day 25 and 68 due to surgery-related complications, development of a trigeminal zoster, or to a persisting frontal brain oedema. Mean follow-up was 49.3 months and all but one patient had a good outcome regardless of surgery-related complications.
Conclusions: Our results suggest that a two-step staged resection of giant OGMs minimizes the increase of postoperative brain oedema as far as possible and translates into lower morbidity and mortality.
Acht kommerzielle Enzymimmunoassay (ELISA)-Testsysteme und ein in.houseHSV-1- und HSV-2-Western blot wurden anhand von 176 mittels Virusisolierung und -typisierung aus korrespondierenden Abstrichen gut charakterisierten Seren auf ihre Eignung zum Nachweis typenspezifischer Antikörper gegen Herpes simplex-Virus (HSV) Typ l und Typ 2 untersucht. Es zeigte sich, daß die auf Vollvirus-Antigenen basierenden ELISAs eine sehr unterschiedliche Sensitivität (85-100% für HSV-1, 35-100% für HSV-2) bei meist nur unzureichender Spezifität (57-93% für HSV-1, 48-91% für HSV-2) erreichen. Hingegen verbindet der einzige ELISA, der das als typspezifisch bekannte HSV-2-Glykoprotein gG-2 als Antigen verwendet, maximale Spezifität (100%) mit mangelnder Sensitivität (52%), wobei insbesondere HSV-l/-2-Koinfektionen nicht erkannt werden. Modifikationen der cut off-Werte konnten die Leistungscharakteristika nicht wesentlich verbessern. Im Western blot ließ sich kein einzelnes HSV-1- bzw. HSV-2-Antigen als optimaler Marker identifizieren, jedoch war bei allen Seren eine eindeutige Zuordnung aufgrund der Reaktivitäts-(Banden-)Muster möglich. Bei Untersuchung von potentiell falsch-positiven „tricky sera"'konnte eine ausreichende Spezifität der acht getesteten IgM-ELISAs lediglich durch Vorbehandlung mit Rheumafaktor-Absorbens erreicht werden. Die Auswertung von 3527 im Rahmen der Routinediagnostik durchgeführten Testungen auf Antikörper gegen HSV-1 und HSV-2 ergab Seroprävalenzraten von durchschnittlich 76,4% für anti-HSV-1 und 12,1% für anti-HSV-2 bei jeweils deutlichem Anstieg mit zunehmendem Alter.
Purpose: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) replicates predominantly in the upper respiratory tract and is primarily transmitted by droplets and aerosols. Taking the medical history for typical COVID-19 symptoms and PCR-based SARS-CoV-2 testing have become established as screening procedures. The aim of this work was to describe the clinical appearance of SARS-CoV-2-PCR positive patients and to determine the SARS-CoV-2 contact risk for health care workers (HCW).
Methods: The retrospective study included n = 2283 SARS-CoV-2 PCR tests from n = 1725 patients with otorhinolaryngological (ORL) diseases performed from March to November 2020 prior to inpatient treatment. In addition, demographic data and medical history were assessed.
Results: n = 13 PCR tests (0.6%) were positive for SARS-CoV-2 RNA. The positive rate showed a significant increase during the observation period (p < 0.01). None of the patients had clinical symptoms that led to a suspected diagnosis of COVID-19 before PCR testing. The patients were either asymptomatic (n = 4) or had symptoms that were interpreted as symptoms typical of the ORL disease or secondary diagnoses (n = 9).
Conclusion: The identification of SARS-CoV-2-positive patients is a considerable challenge in clinical practice. Our findings illustrate that taking a medical history alone is of limited value and cannot replace molecular SARS-CoV-2 testing, especially for patients with ORL diseases. Our data also demonstrate that there is a high probability of contact with SARS-CoV-2-positive patients in everyday clinical practice, so that the use of personal protective equipment, even in apparently “routine cases”, is highly recommended.
NADH: ubiquinone oxidoreductase (complex I) is the first enzyme complex of the respiratory chain. Complex I is a redox-driven proton pump that contributes to the proton motive force that drives ATP synthase. The structure of complex I has been analyzed by x-ray crystallography and electron cryo-microscopy and is now well-described. The ubiquinone (Q) reduction site of complex I is buried in the peripheral arm and a tunnel-like structure is thought to provide access for the hydrophobic substrate from the membrane. Several intermediate binding positions for Q in the tunnel were identified in molecular simulations. Structural data showed the binding of native Q molecules and short chain analogs and inhibitors in the access pathway and in the Q reduction site, respectively. We here review the current knowledge on the interaction of complex I with Q and discuss recent hypothetical models for the coupling mechanism.
Legionella pneumophila, a Gram-negative intracellular bacterium, is one of the major causes of Legionnaires’ disease, a specific type of atypical pneumonia. Despite intensive research efforts that elucidated many relevant structural, molecular and medical insights into Legionella’s pathogenicity, Legionnaires’ disease continues to present an ongoing public health concern. Legionella’s virulence is based on its ability to simultaneously hijack multiple molecular pathways of the host cell to ensure its fast replication and dissemination. Legionella usurps the host ubiquitin system through multiple effector proteins, using the advantage of both conventional and unconventional (phosphoribosyl-linked) ubiquitination, thus providing optimal conditions for its replication. In this review, we summarize the current understanding of L. pneumophila from medical, biochemical and molecular perspectives. We describe the clinical disease presentation, its diagnostics and treatment, as well as host-pathogen interactions, with the emphasis on the ability of Legionella to target the host ubiquitin system upon infection. Furthermore, the interdisciplinary use of innovative technologies enables better insights into the pathogenesis of Legionnaires’ disease and provides new opportunities for its treatment and prevention.
Ubiquitination is a widespread post-translational modification that controls multiple steps in autophagy, a major lysosome-mediated intracellular degradation pathway. A variety of ubiquitin chains are attached as selective labels on protein aggregates and dysfunctional organelles, thus promoting their autophagy-dependent degradation. Moreover, ubiquitin modification of autophagy regulatory components is essential to positively or negatively regulate autophagy flux in both non-selective and selective pathways. We review the current findings that elucidate the components, timing, and kinetics of the multivalent role of ubiquitin signals in control of amplitude and selectivity of autophagy pathways as well as their impact on the development of human diseases.
Ubiquitination, and its control by deubiquitinating enzymes (DUBs), mediates protein stability, function, signaling and cell fate. The ovarian tumor (OTU) family DUB OTULIN (FAM105B) exclusively cleaves linear (Met1-linked) poly-ubiquitin chains and plays important roles in auto-immunity, inflammation and infection. OTULIN regulates Met1-linked ubiquitination downstream of tumor necrosis factor receptor 1 (TNFR1), toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) receptor activation and interacts with the Met1 ubiquitin-specific linear ubiquitin chain assembly complex (LUBAC) E3 ligase. However, despite extensive research efforts, the receptor and cytosolic roles of OTULIN and the distributions of multiple Met1 ubiquitin-associated E3-DUB complexes in the regulation of cell fate still remain controversial and unclear. Apart from that, novel ubiquitin-independent OTULIN functions have emerged highlighting an even more complex role of OTULIN in cellular homeostasis. For example, OTULIN interferes with endosome-to-plasma membrane trafficking and the OTULIN-related pseudo-DUB OTULINL (FAM105A) resides at the endoplasmic reticulum (ER). Here, we discuss how OTULIN contributes to cell fate control and highlight novel ubiquitin-dependent and -independent functions.
Under basal conditions, the proapoptotic protein Bid is a long-lived protein. Pro-apoptotic stimuli such as tumor necrosis factor-alpha (TNFalpha) or Fas induce its caspase-8-mediated cleavage into two fragments. The COOH-terminal cleavage fragment of Bid (tBid) becomes localized to mitochondrial membranes and triggers the release of cytochrome c. Here we show that tBid is ubiquitinated and subsequently degraded by the 26 S proteasome. Degradation of tBid is significantly inhibited by the proteasome inhibitors MG-132 and lactacystin. In contrast, caspase-specific or lysosomal inhibitors do not affect tBid stability. Furthermore, mutation of the putative ubiquitin acceptor sites within tBid results in a stabilized protein as assessed by pulse-chase analysis. To address whether tBid degradation might be regulated by interaction with other Bcl-2-like proteins, cotransfection studies were performed. However, neither the presence of proapoptotic Bax nor antiapoptotic Bcl-2 or Bcl-XL affected tBid degradation. Finally, we determined the functional role of tBid degradation. Overexpression of stabilized tBid proteins significantly enhanced cytochrome c release and subsequent apoptosis induction approximately 2-fold compared with wild type tBid. Similarly, tBid-induced apoptosis was considerably amplified by inhibition of tBid degradation using the proteasome-specific inhibitor MG-132. Thus, proteasomal degradation of tBid limits the extent of apoptosis in living cells.
The inhibitory glycine receptor (GlyR) in developing spinal neurones is internalized efficiently upon antagonist inhibition. Here we used surface labeling combined with affinity purification to show that homopentameric α1 GlyRs generated inXenopus oocytes are proteolytically nicked into fragments of 35 and 13 kDa upon prolonged incubation. Nicked GlyRs do not exist at the cell surface, indicating that proteolysis occurs exclusively in the endocytotic pathway. Consistent with this interpretation, elevation of the lysosomal pH, but not the proteasome inhibitor lactacystin, prevents GlyR cleavage. Prior to internalization, α1 GlyRs are conjugated extensively with ubiquitin in the plasma membrane. Our results are consistent with ubiquitination regulating the endocytosis and subsequent proteolysis of GlyRs residing in the plasma membrane. Ubiquitin-conjugating enzymes thus may have a crucial role in synaptic plasticity by determining postsynaptic receptor numbers.
Oral e-Poster Presentations - Booth 2: Neuro-Oncology C (Imaging&Monitoring), September 27, 2023, 1:00 PM - 2:30 PM
Background: Repetitive TMS (rTMS) can be used to non-invasively map cortical language areas. Commonly, frequencies of 5-10 Hz are used to induce speech errors. We could recently show that frequencies of 30 and 50 Hz are advantageous to achieve higher reliability. However, high-frequent rTMS applied over perisylvian regions still suffer from limited tolerability. Using short-train or paired-pulse TMS (pp-TMS) might offer a good alternative to rTMS to interfere with speech production. In this study, we, therefore, compared 30 Hz rTMS to pp-TMS aiming at improved language mapping.
Methods: 13 healthy, right-handed subjects (f=6, 25-41 years) were investigated using two different rTMS protocols: (i) 30 Hz rTMS and (ii) pp-TMS. TMS protocols were applied in a pseudo-randomized order during a picture naming task (picture-to-trigger interval: 0 ms) over cortical language areas. In a subsequent study, we compared pp-TMS also to short trains of three TMS pulses and repetitive paired pulse TMS. Language errors were post-hoc analysed by two independent raters and were assigned to eight different error categories. The level of pain was assessed on a subjective 0-10 numeric rating scale (NRS). Moreover, language error distribution was analysed using a cortical parcellation system.
Results: 30 Hz rTMS evoked a significantly higher number of errors than the pp-protocol, i.e., 18 ± 12 % vs. 10 ± 7 % (p<0.05). However, pp-TMS was significantly better tolerated with a mean NRS of 2.3 ± 1.6 vs. 3.4 ± 1.5 (p<0.05, FDR-corrected). Of note, pp-TMS could induce a higher number of anomias (15 ± 15 %) than repetitive TMS protocols (4 ± 7 %; p<0.1, FDR-corrected), but less dysarthria. The cortical distribution of errors differed between the two protocols. The results of train-of-three TMS were similar to the pp-TMS protocol.
Conclusions: Due to its better tolerability, pp-TMS might offer the possibility to stimulate regions which are particularly prone to direct facial / trigeminal nerve stimulation, e.g., the inferior frontal gyrus. Moreover, pp-TMS seems advantageous for mapping patients who are comparatively susceptible to rTMS side effects and with regard to safety in general.
In dieser Dissertation wird der Frage nachgegangen, inwiefern sich unangemessene Behandlung in der praktischen Ausbildung zwischen Medizinstudierenden und Studierenden anderer Studienfächer unterscheidet. Zudem wird untersucht, welcher Einfluss der Hierarchie im angestrebten Beruf von den Probanden diesbezüglich zugemessen wird. Auch wird untersucht, wie sich Persönlichkeitsmerkmale auf die Wahrscheinlichkeit, unangemessene Behandlung zu erleben, auswirken.
The mammalian target of rapamycin and the integrated stress response are central cellular hubs regulating translation upon stress. The precise proteins and pathway specificity of translation targets of these pathways remained largely unclear. We recently described a new method for quantitative translation proteomics and found that both pathways control translation of the same sets of proteins.
In the life sciences, there is an ongoing discussion about a perceived ‘reproducibility crisis’. However, it remains unclear to which extent the perceived lack of reproducibility is the consequence of issues that can be tackled and to which extent it may be the consequence of unrealistic expectations of the technical level of reproducibility. Large-scale, multi-institutional experimental replication studies are very cost- and time-intensive. This Perspective suggests an alternative, complementary approach: meta-research using sociological and philosophical methodologies to examine researcher trust in data. An improved understanding of the criteria used by researchers to judge data reliability will provide crucial, initial evidence on the actual scale of the reproducibility crisis and on measures to tackle it.
Human behaviour is inextricably linked to the interaction of emotion and cognition. For decades, emotion and cognition were perceived as separable processes, yet with mutual interactions. Recently, this differen-tiation has been challenged by more integrative approaches, but without addressing the exact neurophysiological basis of their interaction. Here, we aimed to uncover neurophysiological mechanisms of emotion-cognition interaction. We used an emotional Flanker task paired with EEG/FEM beamforming in a large cohort (N=121) of healthy human participants, obtaining high temporal and fMRI-equivalent spatial resolution. Spatially, emotion and cognition processing overlapped in the right inferior frontal gyrus (rIFG), specifically in pars triangularis. Temporally, emotion and cognition processing overlapped during the transition from emotional to cognitive processing, with a stronger interaction in β-band power leading to worse behavioral performance. Despite functionally segregated subdivisions in rIFG, frequency-specific information flowed extensively within IFG and top-down to visual areas (V2, Precuneus) – explaining the behavioral interference effect. Thus, for the first time we here show the neural mechanisms of emotion-cognition interaction in space, time, frequency and information transfer with high temporal and spatial resolution, revealing a central role for β-band activity in rIFG. Our results support the idea that rIFG plays a broad role in both inhibitory control and emotional interference inhibition as it is a site of convergence in both processes. Furthermore, our results have potential clinical implications for understanding dysfunctional emotion-cognition interaction and emotional interference inhibition in psychiatric disor-ders, e.g. major depression and substance use disorder, in which patients have difficulties in regulating emotions and executing inhibitory control.
LFA-1 (Lymphocyte function-associated antigen-1) is a heterodimeric integrin (CD11a/CD18) present on the surface of all leukocytes; it is essential for leukocyte recruitment to the site of tissue inflammation, but also for other immunological processes such as T cell activation and formation of the immunological synapse. Absent or dysfunctional expression of LFA-1, caused by mutations in the ITGB2 (integrin subunit beta 2) gene, results in a rare immunodeficiency syndrome known as Leukocyte adhesion deficiency type I (LAD I). Patients suffering from severe LAD I present with recurrent infections of the skin and mucosa, as well as inflammatory symptoms complicating the clinical course of the disease before and after allogeneic hematopoietic stem cell transplantation (alloHSCT); alloHSCT is currently the only established curative treatment option. With this review, we aim to provide an overview of the intrinsic role of inflammation in LAD I.
Small bowel endoscopy is indicated for patients with an unidentified bleeding site in esophagogastroduodenoscopy and ileocolonoscopy and symptoms of intestinal blood loss or unexplained anemia. In approximately two-thirds of these cases, capsule endoscopy (CE) detects a lesion within the small bowel that explains the patient's symptoms. In few cases, though, lesions outside of the small bowel might be revealed by CE. Therefore, attention to all intestines that are visualized by CE might be necessary not to overlook bleeding sites that had not been discovered by prior flexible endoscopy.
Here the case of a 71-year-old male patient with unexplained anemia is presented by the authors. Small-bowel CE revealed minor bleeding from a neoplastic mass in the cecum. The final diagnosis of an adenocarcinoma of the ascending colon was established after the patient underwent a right hemicolectomy. This article is part of an expert video encyclopedia.
Recently, significant advances have been made by identifying the levels of synchronicity of the underlying dynamics of a given brain state. This research has demonstrated that unconscious dynamics tend to be more synchronous than those found in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that the different brain states are always underpinned by spatiotemporal chaos but with dissociable turbulent dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep, and disorders of consciousness after coma) and were able to distinguish between them using complementary model-free and model-based measures of turbulent information transmission. Our model-free approach used recent advances describing a measure of information cascade across spatial scales using tools from turbulence theory. Complementarily, our model-based approach used exhaustive in silico perturbations of whole-brain models fitted to the empirical neuroimaging data, which allowed us to study the information encoding capabilities of the brain states. Overall, the current framework demonstrates that different levels of turbulent dynamics are fundamental for describing and differentiating between brain states.
Significant advances have been made by identifying the levels of synchrony of the underlying dynamics of a given brain state. This research has demonstrated that non-conscious dynamics tend to be more synchronous than in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that different brain states are underpinned by dissociable spatiotemporal dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep and disorders of consciousness after coma). The model-free approach was based on Kuramoto’s turbulence framework using coupled oscillators. This was extended by a measure of the information cascade across spatial scales. Complementarily, the model-based approach used exhaustive in silico perturbations of whole-brain models fitted to these measures. This allowed studying of the information encoding capabilities in given brain states. Overall, this framework demonstrates that elements from turbulence theory provide excellent tools for describing and differentiating between brain states.
Due to their physiological role in removing damaged cells, natural killer (NK) cells represent ideal candidates for cellular immunotherapy in the treatment of cancer. Thereby, the cytotoxicity of NK cells is regulated by signals on both, the NK cells as well as the targeted tumor cells, and the interplay and balance of these signals determine the killing capacity of NK cells. One promising avenue in cancer treatment is therefore the combination of NK cell therapy with agents that either help to increase the killing capacity of NK cells or sensitize tumor cells to an NK cell-mediated attack. In this mini-review, we present different strategies that can be explored to unleash the potential of NK cell immunotherapy. In particular, we summarize how modulation of apoptosis signaling within tumor cells can be exploited to sensitize tumor cells to NK cell-mediated cytotoxicity.
Introduction: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The “network of excellence on Community Acquired Pneumonia” (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research.
Methods: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat.
Results: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications.
Conclusion: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients’ risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP.