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Zeiner, Pia Susan ; Brandhofe, Annemarie ; Müller-Eschner, Monika ; Steinmetz, Helmuth ; Pfeilschifter, Waltraud
Objective: Area postrema (AP) syndrome (defined as: nausea and/or emesis and/or singultus at onset of brainstem dysfunction) comprises complex pathophysiologic mechanisms triggered by different entities. The first objective was to assess the frequency of AP syndrome as a clinical feature in brainstem encephalitis (BE). Finding an especially high prevalence of AP syndrome in Bickerstaff brainstem encephalitis (BBE), we also analyzed the frequency of AP syndrome in other autoimmune diseases with anti‐ganglioside antibodies (Guillain–Barré syndrome (GBS) and its variants).
Methods: We systematically evaluated the prevalence of AP syndrome in BE in all patients treated at our university hospital during a 15‐year period. In a second step, BBE patients were compared to GBS and Miller Fisher syndrome (MFS) patients as clinical subtypes of a disease continuum without brainstem dysfunction.
Results: We found AP syndrome in 8 of 21 BE patients, including 3 of 7 BBE and in 4 of 112 GBS/MFS patients. AP syndrome was as a frequent but under‐recognized feature of BE with a significant impact on patients’ well being.
Interpretation: Manifestation of AP syndrome in BBE but also in GBS and its subtypes point toward a role of autoimmune antibodies that should be investigated in future studies. Considerable misdiagnosis or nonrecognition complicates diagnostic and therapeutic management. Therefore, AP syndrome should be considered in any episode of otherwise unexplained nausea, emesis, or singultus.
Chen, Pinjie ; Wu, Chunlei ; Huang, Minghua ; Jin, Guangjian ; Shi, Qinglei ; Han, Zhihua ; Chen, Chun
Aims. To investigate the correlation between the apparent diffusion coefficient (ADC) value and cervical intervertebral disc degeneration in adult symptomatic patients.
Methods. A total of 52 symptomatic and 40 healthy volunteers were included. DWI and routine MRI examinations were performed to their cervical spines. The cervical discs (from C2-C3 to C6-C7) were graded according to the Pfirrmann grading system, and ADC values of the nucleus pulposus (NP) were measured. Differences of the ADC values between different genders and anatomic levels were analyzed; the correlation between the ADC value and the Pfirrmann grade was investigated. The cut-off ADC values of each Pfirrmann grade were calculated.
Results. The mean ADC value of the NP decreased with increasing Pfirrmann grade (I–V) upon both patients and asymptotic volunteers. The ADC value decreased descendingly from C2-C3 to C5-C6 (P<0.05) and then increased at C6-C7 (P<0.05). Additionally, the comparison of the ADC values between different genders achieved statistical significance at each anatomical level (P<0.05), except at C6-C7 (P<0.05). Significant negative correlations between the ADC value and either age or Pfirrmann grade were observed.
Conclusions. Our preliminary findings suggest that the ADC value obtained by DWI can provide a reliable indicator to evaluate the cervical disc degeneration.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Kleiter, Ingo ; Gahlen, Anna ; Borisow, Nadja ; Fischer, Katrin ; Wernecke, Klaus-Dieter ; Hellwig, Kerstin ; Pache, Florence ; Ruprecht, Klemens ; Havla, Joachim ; Kümpfel, Tania ; Aktas, Orhan ; Hartung, Hans-Peter ; Ringelstein, Marius ; Geis, Christian ; Kleinschnitz, Christoph ; Berthele, Achim ; Hemmer, Bernhard ; Angstwurm, Klemens ; Stellmann, Jan-Patrick ; Schuster, Simon ; Stangel, Martin ; Lauda, Florian ; Tumani, Hayrettin ; Mayer, Christoph ; Krumbholz, Markus ; Zeltner, Lena ; Ziemann, Ulf ; Linker, Ralf ; Schwab, Matthias ; Marziniak, Martin ; Then Bergh, Florian ; Hofstadt-van Oy, Ulrich ; Neuhaus, Oliver ; Zettl, Uwe K. ; Faiss, Jürgen Hartmut ; Wildemann, Brigitte ; Paul, Friedemann ; Jarius, Sven ; Trebst, Corinna
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
Kristof, Katalin ; Büttner, Benedikt ; Grimm, Anna ; Mewes, Caspar ; Schmack, Bastian ; Popov, Aron-Frederik ; Ghadimi, Michael ; Beißbarth, Tim ; Hinz, José-Maria ; Bergmann, Ingo ; Mansur, Ashham
Objective: The mortality associated with sepsis remains unacceptably high, despite modern high-quality intensive care. Based on the results from previous studies, anaemia and its management in patients with sepsis appear to impact outcomes; however, the transfusion policy is still being debated, and the ideal approach may be extremely specific to the individual. This study aimed to investigate the long-term impact of anaemia requiring red blood cell (RBC) transfusion on mortality and disease severity in patients with sepsis. We studied a general surgical intensive care unit (ICU) population, excluding cardiac surgery patients. 435 patients were enrolled in this observational study between 2012 and 2016.
Results: Patients who received RBC transfusion between 28 days before and 28 days after the development of sepsis (n = 302) exhibited a significantly higher 90-day mortality rate (34.1% vs 19.6%; P = 0.004, Kaplan–Meier analysis). This association remained significant after adjusting for confounders in the multivariate Cox regression analysis (hazard ratio 1.68; 95% confidence interval 1.03–2.73; P = 0.035). Patients who received transfusions also showed significantly higher morbidity scores, such as SOFA scores, and ICU lengths of stay compared to patients without transfusions (n = 133). Our results indicate that anaemia and RBC transfusion are associated with unfavourable outcomes in patients with sepsis.
An ontology-based method for assessing batch effect adjustment approaches in heterogeneous datasets
(2018)
Schmidt, Florian ; List, Markus ; Cukuroglu, Engin ; Köhler, Sebastian ; Göke, Jonathan ; Schulz, Marcel Holger
Motivation: International consortia such as the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA) or the International Human Epigenetics Consortium (IHEC) have produced a wealth of genomic datasets with the goal of advancing our understanding of cell differentiation and disease mechanisms. However, utilizing all of these data effectively through integrative analysis is hampered by batch effects, large cell type heterogeneity and low replicate numbers. To study if batch effects across datasets can be observed and adjusted for, we analyze RNA-seq data of 215 samples from ENCODE, Roadmap, BLUEPRINT and DEEP as well as 1336 samples from GTEx and TCGA. While batch effects are a considerable issue, it is non-trivial to determine if batch adjustment leads to an improvement in data quality, especially in cases of low replicate numbers.
Results: We present a novel method for assessing the performance of batch effect adjustment methods on heterogeneous data. Our method borrows information from the Cell Ontology to establish if batch adjustment leads to a better agreement between observed pairwise similarity and similarity of cell types inferred from the ontology. A comparison of state-of-the art batch effect adjustment methods suggests that batch effects in heterogeneous datasets with low replicate numbers cannot be adequately adjusted. Better methods need to be developed, which can be assessed objectively in the framework presented here.
Königs, Christoph ; Schultze-Straßer, Stephan ; Quaiser, Andrea ; Bochennek, Konrad ; Schwabe, Dirk ; Klingebiel, Thomas ; Köhl, Ulrike ; Cappel, Claudia ; Rolle, Udo ; Bader, Peter ; Bremm, Melanie ; Hünecke, Sabine ; Bakhtiar, Shahrzad
B lymphocytes are key players in humoral immunity, expressing diverse surface immunoglobulin receptors directed against specific antigenic epitopes. The development and profile of distinct subpopulations have gained awareness in the setting of primary immunodeficiency disorders, primary or secondary autoimmunity and as therapeutic targets of specific antibodies in various diseases. The major B cell subpopulations in peripheral blood include naïve (CD19+ or CD20+IgD+CD27−), non-switched memory (CD19+ or CD20+IgD+CD27+) and switched memory B cells (CD19+ or CD20+IgD−CD27+). Furthermore, less common B cell subpopulations have also been described as having a role in the suppressive capacity of B cells to maintain self-tolerance. Data on reference values for B cell subpopulations are limited and only available for older age groups, neglecting the continuous process of human B cell development in children and adolescents. This study was designed to establish an exponential regression model to produce continuous reference values for main B cell subpopulations to reflect the dynamic maturation of the human immune system in healthy children.
Always forward, never back
(2018)
Stem cells are the therapeutics of the future, but to use them to their full potential we first need to understand how they function within the body. Professor Michael Rieger of the Goethe University Hospital, Frankfurt, Germany is working to understand the complex intricacies of stem cell replication and behaviour.
Siebers, Kathrin ; Fink, Bijan ; Zakrzewicz, Anna ; Agné, Alisa ; Richter, Katrin ; Konzok, Sebastian ; Hecker, Andreas ; Zukunft, Sven ; Küllmar, Mira ; Klein, Jochen ; McIntosh, J. Michael ; Timm, Thomas ; Sewald, Katherina ; Padberg, Winfried ; Aggarwal, Nupur ; Chamulitrat, Walee ; Santoso, Sentot ; Xia, Wendy ; Janciauskiene, Sabina ; Grau, Veronika
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
Alirocumab reduces total nonfatal cardiovascular and fatal events: The ODYSSEY OUTCOMES trial
(2018)
Szarek, Michael ; White, Harvey ; Schwartz, Gregory G. ; Alings, Marco ; Bhatt, Deepak L. ; Bittner, Vera ; Chiang, Chern-En ; Diaz, Rafael ; Edelberg, Jay M. ; Goodman, Shaun G. ; Hanotin, Corinne ; Harrington, Robert A. ; Jukema, J. Wouter ; Kimura, Takeshi ; Kiss, Robert Gabor ; Lecorps, Guillaume ; Mahaffey, Kenneth ; Moryusef, Angèle ; Pordy, Robert ; Roe, Matthew T. ; Tricoci, Pierluigi ; Xavier, Denis ; Zeiher, Andreas M. ; Steg, P. Gabriel
Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.
Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.
Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.
Results: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.
Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.
Background and Aims: Intoxications by aliphatic halogenated hydrocarbons (AHH), used as effective solvents, are rare and may cause life-threatening liver injury. Patients with acute intoxications by AHH received an innovative treatment.
Methods: Analyzed were data of 60 patients intoxicated by AHH, such as dichloromethane (n = 3), chloroform (n = 2), carbon tetrachloride (n = 12), 1,2-dichloroethane (n = 18), 1,1,2-trichloroethane (n = 2), trichloroethylene (n = 2), tetrachloroethylene (n = 13) or mixed AHH chemicals (n = 8), who received a new treatment consisting of CO2-induced hyperventilation to accelerate toxin removal via the lungs.
Results: Added to the inspiration air at a flow rate of 2–3 Liter min−1, CO2 increased the respiratory volume up to 25–30 Liter min−1, ensuring forced AHH exhalation. This CO2-induced hyperventilation therapy was commonly well tolerated by the 60 patients and lasted for 106.0±10.5 hours. In most cases, initially increased liver test results of aminotransferases normalized quickly under the therapy, and liver histology obtained at completion of the therapy revealed, in the majority of patients, normal findings or fatty changes, and rarely severe single cell necrosis but no confluent liver cell necrosis. Despite therapy, clinical outcome was unfavorable for 4/60 patients (6.7%) of the study cohort, due to single or combined risk factors. These included late initiation of the CO2-induced hyperventilation therapy, intentional intoxication, uptake of high amounts of AHH, concomitant ingestion of overdosed drugs, consumption of high amounts of alcohol, and history of alcohol abuse.
Conclusions: For intoxications by AHH, effective therapy approaches including forced hyperventilation to increase toxin removal via the lungs are available and require prompt initiation.
Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma
(2018)
Ronellenfitsch, Michael Wilfried ; Zeiner, Pia Susan ; Mittelbronn, Michel Guy André ; Urban, Hans ; Pietsch, Torsten ; Reuter, Dirk ; Senft, Christian ; Steinbach, Joachim Peter ; Westphal, Manfred ; Harter, Patrick Nikolaus
Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an established pharmacological activator of AMP-activated protein kinase (AMPK). Both, AICAR and AMPK were reported to attenuate inflammation. However, AICAR is known for many AMPK-independent effects, although the mechanisms remain incompletely understood. Here we report a potent suppression of lipopolysaccharide (LPS)-induced inflammatory gene expression by AICAR in primary human macrophages, which occurred independently of its conversion to AMPK-activating 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate. Although AICAR did not interfere with activation of cytosolic signalling cascades and nuclear translocation of nuclear factor - κB (NFκB) by LPS, it prevented the recruitment of NFκB and RNA polymerase II to target gene promoters. AICAR also inhibited signal transducer and activator of transcription 3 (STAT3)-dependent induction of interleukin (IL) IL-6 and IL-10 targets, while leaving STAT6 and HIF1α-dependent gene expression in IL-4 and dimethyloxalylgylcine-treated macrophages intact. This points to a transcription factor-specific mode of action. Attenuated gene expression correlated with impaired NFκB and STAT3, but not HIF-binding in electrophoretic mobility shift assays in vitro. Conclusively, AICAR interferes with DNA binding of NFκB and STAT3 to modulate inflammatory responses.
Manig, Anja ; Ribes, Sandra ; Diesselberg, Catharina ; Bunkowski, Stephanie ; Nau, Roland ; Schütze, Sandra
In order to elucidate the causes for the increased mortality of aged patients with bacterial central nervous system (CNS) infections, we compared the course of Streptococcus pneumoniae (S. pneumoniae) meningitis in aged and young mice. Aged (21.2 ± 3.1 months, n = 40) and young (3.2 ± 0.9 months, n = 42) C57BL/6N and B6/SJL mice were infected by intracerebral injection of 50–70 CFU S. pneumoniae serotype 3 and monitored for 15 days. Aged and young mice did not differ concerning mortality (35% versus 38%), weight loss, development of clinical symptoms, bacterial concentrations in cerebellum and spleen as well as the number of leukocytes infiltrating the CNS. In contrast to results from our geriatric mouse model of Escherichia coli (E. coli) meningitis, where aged mice showed a higher mortality and an impaired elimination of bacteria, we did not find any differences between aged and young mice after intracerebral infection with S. pneumoniae serotype 3. This indicates that the increased susceptibility of aged mice to bacterial CNS infections is pathogen-specific: It appears less prominent in infections caused by hardly phagocytable pathogens with thick capsules like S. pneumoniae serotype 3, where the age-related decline of the phagocytic capacity of microglia and macrophages has a minor influence on the disease course.
Purpose: There is some controversy whether or not saccades change with age. This cross-sectional study aims to clarify the characteristics of reflexive saccades at various ages to establish a normative cohort in a standardized set-up. Second objective is to investigate the feasibility of saccadometry in daily ophthalmological practice.
Methods: One hundred healthy participants aged between 6 and 76 years underwent an ophthalmologic examination and saccadometry, using an infrared video-oculography device, sampling at 220 Hz. The reflexive saccades were evoked in four directions and three target displacements each (5°/15°/30° horizontally and of 5°/10°/20° vertically). Saccadic peak velocity, gain (amplitude/target displacement) and latency were measured.
Results: Mean peak velocity of saccades was 213°/s (± 29°/s), 352°/s (± 50°/s) and 455°/s (± 67°/s) to a target position 5°, 15°and 30° horizontally, respectively, and 208°/s (± 36°/s), 303°/s (± 50°/s) and 391°/s (± 71°/s) to a target position 5°, 10° and 20° vertically. The association between peak velocity and eccentricity proved to be present at any age in all four directions. We found no relevant effect of age on peak velocity, gain and latency in a fitted linear mixed model. However, latency becomes shorter during childhood and adolescence, while in adulthood it is relatively stable with a slight trend to increase in the elderly. Saccades are more precise when the target displacement is small. Isometric saccades are most common, followed by hypometric ones. All children and elderly were able to perform good quality saccadometry in a recording time of approximately 10 minutes.
Conclusion: The presented data may serve as normative control for further studies using such a video-oculography device for saccadometry. The means of peak velocity and the gain can be used independently from age respecting the target displacement. Latency is susceptible to age.
Schötterl, Sonja ; Huber, Stephan M. ; Lentzen, Hans ; Mittelbronn, Michel Guy André ; Naumann, Ulrike
Viscum album L. extracts (VE) are applied as complementary cancer therapeutics for more than one century. Extracts contain several compounds like mistletoe lectins (ML) 1-3 and viscotoxins, but also several minor ingredients. Since ML-1 has been described as one of the main active components harboring antitumor activity, purified native or recombinant ML-1 has been also used in clinical trials in the last years. The present study examined and compared the immunoboosting effects of three ML-1 containing drugs (the extract ISCADOR Qu, the recombinant ML-1 Aviscumine, and purified native ML-1) in the context of the T-cell mediated killing of glioma cells. Additionally we examined the possible underlying T-cell stimulating mechanisms. Using cocultures of immune and glioma cells, a PCR-based microarray, quantitative RT-PCR, and an antibody-based array to measure cytokines in blood serum, immunosupporting effects were determined. A highly aggressive, orthotopic, immunocompetent syngeneic mouse glioma model was used to determine the survival of mice treated with ISCADOR Qu alone or in combination with tumor irradiation and temozolomide (TMZ). Treatment of glioblastoma (GBM) cells with ISCADOR Qu that contains a high ML concentration, but also viscotoxins and other compounds, as well as with Aviscumine or native ML-1, enhanced the expansion of cancer cell-specific T-cells as well as T-cell-mediated tumor cell lysis, but to a different degree. In GBM cells all three ML-1-containing preparations modulated the expression of immune response associated genes. In vivo, subcutaneous ISCADOR Qu injections at increasing concentration induced cytokine release in immunocompetent VM/Dk-mice. Finally, ISCADOR Qu, if applied in combination with tumor irradiation and TMZ, further prolonged the survival of glioma mice. Our findings indicate that ML-1 containing drugs enhance anti-GBM immune responses and work in synergy with radiochemotherapy. Therefore, adjuvant mistletoe therapy should be considered as an auspicious treatment option for glioma patients.
Boeckel, Jes-Niels ; Palapies, Lars ; Klotsche, Jens ; Zeller, Tanja ; Jeinsen, Beatrice von ; Perret, Maya Felicitas ; Kleinhaus, Soeren L. ; Pieper, Lars ; Tzikas, Stergios ; Leistner, David ; Bickel, Christoph ; Stalla, Günter K. ; Lehnert, Hendrik ; Lindahl, Bertil ; Wittchen, Hans-Ulrich ; Silber, Sigmund ; Baldus, Stephan ; März, Winfried ; Dimmeler, Stefanie ; Blankenberg, Stefan ; Münzel, Thomas ; Zeiher, Andreas M. ; Keller, Till
The use of cardiac troponins (cTn) is the gold standard for diagnosing myocardial infarction. Independent of myocardial infarction (MI), however, sex, age and kidney function affect cTn levels. Here we developed a method to adjust cTnI levels for age, sex, and renal function, maintaining a unified cut-off value such as the 99th percentile. A total of 4587 individuals enrolled in a prospective longitudinal study were used to develop a model for adjustment of cTn. cTnI levels correlated with age and estimated glomerular filtration rate (eGFR) in males/females with rage = 0.436/0.518 and with reGFR = −0.142/−0.207. For adjustment, these variables served as covariates in a linear regression model with cTnI as dependent variable. This adjustment model was then applied to a real-world cohort of 1789 patients with suspected acute MI (AMI) (N = 407). Adjusting cTnI showed no relevant loss of diagnostic information, as evidenced by comparable areas under the receiver operator characteristic curves, to identify AMI in males and females for adjusted and unadjusted cTnI. In specific patients groups such as in elderly females, adjusting cTnI improved specificity for AMI compared with unadjusted cTnI. Specificity was also improved in patients with renal dysfunction by using the adjusted cTnI values. Thus, the adjustments improved the diagnostic ability of cTnI to identify AMI in elderly patients and in patients with renal dysfunction. Interpretation of cTnI values in complex emergency cases is facilitated by our method, which maintains a single diagnostic cut-off value in all patients.
Wilde, Rudy Leon de ; Wallwiener, Markus ; Di Spiezio Sardo, Attilio ; Tanos, Vasilios ; Becker, Sven
The goal of this special issue is to address research concerning risks and problems related to the diagnosis and therapy of adenomyosis and myomata. During the last years, there have been several controversies in the scientific community regarding these topics. The original papers gathered in this special issue highlight and inform the readers about the innovations made in this field. ...
Grent-'t-Jong, Tineke ; Rivolta, Davide ; Groß, Joachim ; Gajwani, Ruchika ; Lawrie, Stephen M. ; Schwannauer, Matthias ; Heidegger, Tonio ; Wibral, Michael ; Singer, Wolf ; Sauer, Andreas ; Scheller, Bertram ; Uhlhaas, Peter J.
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.
Acute cholecystitis – a cohort study in a real-world clinical setting (REWO study, NCT02796443)
(2018)
Blythe, Jennifer ; Herrmann, Eva ; Faust, Dominik ; Falk, Stephan ; Edwards-Lehr, Tina ; Stockhausen, Florian ; Hanisch, Ernst ; Buia, Alexander
Background: For decades, the optimal timing of surgery for acute cholecystitis has been controversial. Recent meta-analyses and population-based studies favor early surgery. One recent large randomized trial has demonstrated that a delayed approach increases morbidity and cost compared to early surgery within 24 hours of hospital admission. Since cases of severe cholecystitis were excluded from this trial, we argue that these results do not reflect real-world clinical situations. From our point of view, these results were in contrast to the clinical experience with our patients; so, we decided to analyze critically all our patients with the null hypothesis that the patients treated with a delayed cholecystectomy after an acute cholecystitis have a similar or even better outcome than those treated with an early operative approach.
Patients and methods: We retrospectively analyzed clinical data from all patients with cholecystectomies in the period between January 2006 and September 2015. A total of 1,723 patients were categorized into four groups: early (n=138): urgent surgery of patients with acute cholecystitis within the first 72 hours of the onset of symptoms; intermediate (n=297): surgery of patients with acute cholecystitis within an average of 10 days after the onset of symptoms; delayed (n=427): initial non-surgical treatment of acute cholecystitis with surgery performed within 6–12 weeks of the onset of symptoms; and elective (n=868): cholecystectomy within a symptom-free interval of choice in patients with symptomatic cholecystolithiasis without signs of acute cholecystitis.
Results: In a real-world scenario, early/intermediate cholecystectomy in acute cholecystitis was associated with a significant increase in morbidity and mortality (Clavien–Dindo score) compared to a delayed approach with surgery performed 6–12 weeks after the onset of symptoms. The adjusted linear rank statistics showed a decrease in the complication score with values of 2.29 in the early group, 0.48 in the intermediate group, –0.26 in the delayed group and –2.12 in the elective group. The results translate into a continuous decrease of the complication score from early over intermediate and delayed to the elective group.
Conclusion: These results demonstrate that delayed cholecystectomy can be performed safely. In cases with severe cholecystitis, early and/or intermediate approaches still have a relatively high risk of morbidity and mortality.
Pleli, Thomas ; Mondorf, Antonia Maria ; Ferreirós Bouzas, Nerea ; Thomas, Dominique Jeanette ; Dvorak, Karel ; Biondi, Ricardo M. ; Meyer zu Heringdorf, Dagmar ; Zeuzem, Stefan ; Geisslinger, Gerd ; Zimmermann, Herbert ; Waidmann, Oliver ; Piiper, Albrecht
Background/Aims: Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear.
Methods: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA.
Results: Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors). In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors.
Conclusion: Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.