Items 1-20 of 4152

    • Journal Article

      Radiomic Features and Machine Learning for the Discrimination of Renal Tumor Histological Subtypes: A Pragmatic Study Using Clinical-Routine Computed Tomography 

      Uhlig, Johannes; Leha, Andreas; Delonge, Laura M.; Haack, Anna-Maria; Shuch, Brian; Kim, Hyun S.; Bremmer, Felix; Trojan, Lutz; Lotz, Joachim; Uhlig, Annemarie
      Cancers 2020; 12(10) p.1-13: Art. 3010
      This study evaluates the diagnostic performance of radiomic features and machine learning algorithms for renal tumor subtype assessment in venous computed tomography (CT) studies from clinical routine. Patients undergoing surgical resection and histopathological assessment of renal tumors at a tertiary referral center between 2012 and 2019 were included. Preoperative venous-phase CTs from multiple referring imaging centers were segmented, and standardized radiomic features extracted. After preprocessing, class imbalance handling, and feature selection, machine learning algorithms were used to predict renal tumor subtypes using 10-fold cross validation, assessed as multiclass area under the curve (AUC). In total, n = 201 patients were included (73.7% male; mean age 66 ± 11 years), with n = 131 clear cell renal cell carcinomas (ccRCC), n = 29 papillary RCC, n = 11 chromophobe RCC, n = 16 oncocytomas, and n = 14 angiomyolipomas (AML). An extreme gradient boosting algorithm demonstrated the highest accuracy (multiclass area under the curve (AUC) = 0.72). The worst discrimination was evident for oncocytomas vs. AML and oncocytomas vs. chromophobe RCC (AUC = 0.55 and AUC = 0.45, respectively). In sensitivity analyses excluding oncocytomas, a random forest algorithm showed the highest accuracy, with multiclass AUC = 0.78. Radiomic feature analyses from venous-phase CT acquired in clinical practice with subsequent machine learning can discriminate renal tumor subtypes with moderate accuracy. The classification of oncocytomas seems to be the most complex with the lowest accuracy.
      View Document Abstract
    • Journal Article

      3D virtual pathohistology of lung tissue from Covid-19 patients based on phase contrast X-ray tomography 

      Eckermann, Marina; Frohn, Jasper; Reichardt, Marius; Osterhoff, Markus; Sprung, Michael; Westermeier, Fabian; Tzankov, Alexandar; Werlein, Christopher; Kühnel, Mark; Jonigk, Danny; et al.
      Salditt, Tim
      eLife 2020; 9 p.1-25: Art. e60408
      We present a three-dimensional (3D) approach for virtual histology and histopathology based on multi-scale phase contrast x-ray tomography, and use this to investigate the parenchymal architecture of unstained lung tissue from patients who succumbed to Covid-19. Based on this first proof-of-concept study, we propose multi-scale phase contrast x-ray tomography as a tool to unravel the pathophysiology of Covid-19, extending conventional histology by a third dimension and allowing for full quantification of tissue remodeling. By combining parallel and cone beam geometry, autopsy samples with a maximum cross section of 8 mm are scanned and reconstructed at a resolution and image quality, which allows for the segmentation of individual cells. Using the zoom capability of the cone beam geometry, regions-of-interest are reconstructed with a minimum voxel size of 167 nm. We exemplify the capability of this approach by 3D visualization of diffuse alveolar damage (DAD) with its prominent hyaline membrane formation, by mapping the 3D distribution and density of lymphocytes infiltrating the tissue, and by providing histograms of characteristic distances from tissue interior to the closest air compartment.
      View Document Abstract
    • Journal Article

      Generation of homozygous CRISPRa human induced pluripotent stem cell (hiPSC) lines for sustained endogenous gene activation 

      Schoger, Eric; Argyriou, Loukas; Cyganek, Lukas; Zelarayán, Laura Cecilia
      Stem Cell Research 2020; 48 p.1-6: Art. 101944
      CRISPR/Cas9 technology is a powerful tool, owing to its robust on-target activity and high fidelity. Mutated Cas9 without nuclease activity (dCas9) fused to transcriptional modulators, can function as transcriptional inhibitors or activators (CRISPRa). We generated homozygous human induced pluripotent stem cell (hiPSC) lines with an inserted CRISPRa cassette into the AAVS1 locus whilst maintaining pluripotency and genomic integrity, the ability to differentiate into all three germ layers, generate functional cardiomyocytes, and validated Cas9-mediated induction of endogenous gene expression. Our generated hiPSC-CRISPRa offers a valuable tool for studying endogenous transcriptional modulation with single and multiplexed possibilities in all human cell types.
      View Document Abstract
    • Journal Article

      Key components and IT assistance of participant management in clinical research: a scoping review 

      Pung, Johannes; Rienhoff, Otto
      JAMIA Open 2020; 00(0) p.1-10
      Objectives Managing participants and their data are fundamental for the success of a clinical trial. Our review identifies and describes processes that deal with management of trial participants and highlights information technology (IT) assistance for clinical research in the context of participant management. Methods A scoping literature review design, based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, was used to identify literature on trial participant-related proceedings, work procedures, or workflows, and assisting electronic systems. Results The literature search identified 1329 articles of which 111 were included for analysis. Participant-related procedures were categorized into 4 major trial processes: recruitment, obtaining informed consent, managing identities, and managing administrative data. Our results demonstrated that management of trial participants is considered in nearly every step of clinical trials, and that IT was successfully introduced to all participant-related areas of a clinical trial to facilitate processes. Discussion There is no precise definition of participant management, so a broad search strategy was necessary, resulting in a high number of articles that had to be excluded. Nevertheless, this review provides a comprehensive overview of participant management-related components, which was lacking so far. The review contributes to a better understanding of how computer-assisted management of participants in clinical trials is possible.
      View Document Abstract
    • Journal Article

      SARS-CoV-2, immunosenescence and inflammaging: partners in the COVID-19 crime 

      Domingues, Renato; Lippi, Alice; Setz, Cristian; Outeiro, Tiago F.; Krisko, Anita
      Aging 2020; 12(18) p.18778-18789
      Pneumonia outbreak in the city of Wuhan, China, prompted the finding of a novel strain of severe acute respiratory syndrome virus (SARS-CoV-2). Here, we discuss potential long-term consequences of SARS-CoV-2 infection, and its possibility to cause permanent damage to the immune system and the central nervous system. Advanced chronological age is one of the main risk factors for the adverse outcomes of COVID-19, presumably due to immunosenescence and chronic low-grade inflammation, both characteristic of the elderly. The combination of viral infection and chronic inflammation in advanced chronological age might cause multiple detrimental unforeseen consequences for the predisposition and severity of neurodegenerative diseases and needs to be considered so that we can be prepared to deal with future outcomes of the ongoing pandemic.
      View Document Abstract
    • Journal Article

      COVID-19: scientific reasoning, pragmatism and emotional bias 

      Gattinoni, Luciano; Marini, John J.; Chiumello, Davide; Busana, Mattia; Camporota, Luigi
      Annals of Intensive Care. 2020 Oct 12;10(1):134
      View Document
    • Journal Article

      Correction to: Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle 

      Dammann, Insa; Wemheuer, Wiebke M.; Wrede, Arne; Wemheuer, Wilhelm E.; Campe, Amely; Petschenka, Jutta; Schulze-Sturm, Ulf; Hahmann, Uwe; Czerny, Claus P.; Münster, Pia; et al.
      Brenig, BertramKreienbrock, LotharHerden, ChristianeSchulz-Schaeffer, Walter J.
      Veterinary Research. 2020 Oct 15;51(1):130
      An amendment to this paper has been published and can be accessed via the original article.
      View Document Abstract
    • Journal Article

      Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers—results from the DELCODE study 

      Sannemann, Lena; Schild, Ann-Katrin; Altenstein, Slawek; Bartels, Claudia; Brosseron, Frederic; Buerger, Katharina; Cosma, Nicoleta C.; Fliessbach, Klaus; Freiesleben, Silka D.; Glanz, Wenzel; et al.
      Heneka, Michael T.Janowitz, DanielKilimann, IngoKobeleva, XeniaLaske, ChristophMetzger, Coraline D.Munk, Matthias H. J.Perneczky, RobertPeters, OliverPolcher, AlexandraPriller, JosefRauchmann, BorisRösch, ChristinaRudolph, JannaSchneider, AnjaSpottke, AnnikaSpruth, Eike JTeipel, StefanVukovich, RuthWagner, MichaelWiltfang, JensWolfsgruber, SteffenDuezel, EmrahJessen, Frank
      Alzheimer's Research & Therapy. 2020 Oct 16;12(1):131
      Background Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer’s disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries. Methods We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries. Results The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996–1.000, p < .05). Conclusion These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline. Trial registration German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.
      View Document Abstract
    • Journal Article

      Training improves the handling of inhaler devices and reduces the severity of symptoms in geriatric patients suffering from chronic-obstructive pulmonary disease 

      Luley, Marie-Christine; Loleit, Tobias; Knopf, Elmar; Djukic, Marija; Criée, Carl-Peter; Nau, Roland
      BMC Geriatrics. 2020 Oct 09;20(1):398
      Purpose Elderly patients with impaired vision, cognitive decline or motor/sensory disturbances of their fingers suffering from chronic-obstructive pulmonary disease (COPD) encounter difficulties in handling inhaler devices used as the cornerstones of treatment of pulmonary obstruction. Many elderly patients make severe mistakes which impede adequate drug delivery to the bronchioles. This multimodal training program was designed to reduce the number of handling mistakes of inhaler devices. Methods From October 1, 2016 to September 30, 2017, a prospective intervention study was conducted in 38 in-patients > 65 years (median age 79 years) with previously diagnosed COPD. The effect of an 8-day intervention comprising daily counselling and video demonstration according to the recommendations of the German Airway League on the frequency of mistakes during handling of inhaler devices, the forced expiratory volume in 1 s (FEV1), the forced vital capacity (FVC) and the perception of symptoms (COPD Assessment Test, CAT) were studied. Measurements on days 1 and 8 were compared by Wilcoxon signed rank test. Results The number of handling mistakes per patient decreased as a consequence of the intervention from 3.0 (0–7) to 0.5 (0–6) [median (minimum-maximum; p < 0.0001)]. The CAT Score decreased from 19.5 (14/24) to 14.5 (10.75/21) [median (25./75. percentile; p < 0.0001) indicating a substantial reduction of clinical symptoms. Conversely, FEV1 and FVC only slightly increased (difference statistically not significant). At study entry, the number of handling mistakes was inversely correlated with the Mini Mental Status Test (MMST) score (p = 0.01). The reduction of the number of handling mistakes during the intervention was not correlated with the MMST. Conclusion In COPD, intensive training for 8 days improved the handling of inhalers and reduced clinical symptoms in geriatric patients. Patients with cognitive abnormalities also benefitted from this intervention. Trial registration German Clinical Trials Registry DRKS00023196 , date of registration September 29, 2020 (retrospectively registered).
      View Document Abstract
    • Journal Article

      Syndecan-4 as a Marker of Endothelial Dysfunction in Patients with Resistant Hypertension 

      Lipphardt, Mark; Dihazi, Hassan; Maas, Jens-Holger; Schäfer, Ann-Kathrin; Amlaz, Saskia I.; Ratliff, Brian B.; Koziolek, Michael J.; Wallbach, Manuel
      Journal of Clinical Medicine 2020; 9(9) p.1-15: Art. 3051
      (1) Background: Arterial hypertension (HTN) is one of the most relevant cardiovascular risk factors. Nowadays multiple pharmaceutical treatment options exist with novel interventional methods (e.g., baroreflex activation therapy (BAT)) as a last resort to treat patients with resistant HTN. Although pathophysiology behind resistant HTN is still not fully understood. There is evidence that selected biomarkers may be involved in the pathophysiology of HTN. (2) Methods: We investigated serum SDC4-levels in patients suffering from resistant HTN before and 6 months after BAT implantation. We collected 19 blood samples from patients with resistant HTN and blood pressure above target and measured serum SDC4-levels. (3) Results: Our results showed high serum SDC4-levels in patients with resistant HTN as compared to a healthy population. Patients with both, resistant HTN and diabetes mellitus type II, demonstrated higher serum SDC4-levels. β-blockers had lowering effects on serum SDC4-levels, whereas calcium channel blockers were associated with higher levels of serum SDC4. BAT implantation did not lead to a significant difference in serum SDC4-levels after 6 months of therapy. (4) Conclusion: Based on our results we propose SDC4 is elevated in patients suffering from resistant HTN. Thus, SDC4 might be a potential marker for endothelial dysfunction in patients with resistant hypertension.
      View Document Abstract
    • Journal Article

      Pulmonary vein ablation in a patient with a large left common pulmonary vein joining a large right common trunk 

      Bengel, Philipp; Herting, Jonas; Zabel, Markus; Lüthje, Lars
      European Heart Journal - Case Reports: Art. 1
      View Document
    • Journal Article

      Higher galectin-3 levels are independently associated with lower anxiety in patients with risk factors for heart failure 

      Sadlonova, Monika; Meyer, Thomas; Binder, Lutz; Wachter, Rolf; Edelmann, Frank; Herrmann-Lingen, Christoph
      BioPsychoSocial Medicine. 2020 Oct 02;14(1):24
      Background Galectin-3 promotes the proliferation of neural progenitor cells and is engaged in cell-cell adhesion, cell-matrix interactions, and macrophage activation. In addition, in patients with heart failure this carbohydrate-binding protein is a known prognostic marker for cardiovascular mortality. However, its association with psychological variables has not been investigated so far. Methods Using data from the multicenter, observational Diast-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) trial, we studied in participants with cardiovascular risk factors (n = 1260, age 66.7 ± 8.0 years, males 51%, left ventricular ejection fraction 60.0 ± 8.1%) the relationship between serum concentrations of galectin-3 and anxiety. Galectin-3 levels were measured by means of a sandwich enzyme-linked immunosorbent assay, and anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS). Results In univariate analysis, there was a weak but significant inverse correlation between galectin-3 and HADS anxiety (rho = − 0.076; p = 0.008). Linear regression models adjusted for sex, age, body-mass index, estimated glomerular filtration rate, left ventricular ejection fraction, 6-min walking distance, the 36-item Short-Form Health Survey (SF-36) subscale physical functioning, and known biomarkers for heart failure confirmed that serum galectin-3 significantly and independently predicted self-rated anxiety (B = -2.413; 95%CI = -2.413–-4.422; p = 0.019). Conclusion In patients with cardiovascular risk factors, serum concentrations of galectin-3 showed an inverse association with anxiety, which was independent of both the severity of physical impairment and established risk factors for the progression of heart failure.
      View Document Abstract
    • Journal Article

      $^{18}$F-FDG-PET in Mouse Models of Alzheimer's Disease 

      Bouter, Caroline; Bouter, Yvonne
      Frontiers in Medicine 2019; 6 p.1-9: Art. 71
      Suitable animal models and in vivo biomarkers are essential for development and evaluation of new therapeutic strategies in Alzheimer's disease (AD). $^{18}$F-Fluorodeoxyglucose (18F-FDG)-positron-emission tomography (PET) is an imaging biomarker that allows the assessment of cerebral glucose metabolism in vivo. While $^{18}$F-FDG-PET/CT is an established tool in the evaluation of AD patients, its role in preclinical studies with AD mouse models remains unclear. Here, we want to review available studies on $^{18}$F-FDG-PET/CT in AD mouse models in order to evaluate the method and its impact in preclinical AD research. Only a limited number of studies using $^{18}$F-FDG-PET in AD mice were carried out so far showing contradictory findings in cerebral FDG uptake. Methodological differences as well as underlying pathological features of used mouse models seem to be accountable for those varying results. However, $^{18}$F-FDG-PET can be a valuable tool in longitudinal in vivo therapy monitoring with a lot of potential for future studies.
      View Document Abstract
    • Journal Article

      Epigenetic Control of IFN-γ Host Responses During Infection With Toxoplasma gondii 

      Nast, Roswitha; Choepak, Tenzin; Lüder, Carsten G. K.
      Frontiers in Immunology 2020; 11 p.1-15: Art. 581241
      Host defense against the human pathogen Toxoplasma gondii depends on secretion of interferon (IFN)-γ and subsequent activation of monocytic cells to combat intracellular parasites. Previous studies have shown that T. gondii evades IFN-γ-mediated immunity by secreting the effector TgIST into the host cell where it binds to STAT1, strengthens its DNA binding activity and recruits the Mi-2/NuRD complex to STAT1-responsive promoters. Here we investigated the impact of the host chromatin environment on parasite interference with IFN-γ-induced gene expression. Luciferase reporters under control of primary and secondary IFN-γ response promoters were only inhibited by T. gondii when they were stably integrated into the host genome but not when expressed from a plasmid vector. Absence of CpG islands upstream and/or downstream of the transcriptional start site allowed more vigorous up-regulation by IFN-γ as compared to CpG-rich promoters. Remarkably, it also favored parasite interference with IFN-γ-induced gene expression indicating that nucleosome occupancy at IFN-γ-responsive promoters is important. Promoter DNA of IFN-γ-responsive genes remained largely non-methylated in T. gondii-infected cells, and inhibition of DNA methylation did not impact parasite interference with host responses. IFN-γ up-regulated histone marks H4ac, H3K9ac, and H3K4me3 but down-regulated H3S10p at primary and secondary response promoters. Infection with T. gondii abolished histone modification, whereas total nuclear activities of histone acetyl transferases and histone deacetylases were not altered. Taken together, our study reveals a critical impact of the host chromatin landscape at IFN-γ-activated promoters on their inhibition by T. gondii with a comprehensive blockade of histone modifications at parasite-inactivated promoters.
      View Document Abstract
    • Journal Article

      Ostarine and Ligandrol Improve Muscle Tissue in an Ovariectomized Rat Model 

      Roch, Paul Jonathan; Henkies, Danny; Carstens, Jan Christoph; Krischek, Carsten; Lehmann, Wolfgang; Komrakova, Marina; Sehmisch, Stephan
      Frontiers in Endocrinology 2020; 11 p.1-12: Art. 556581
      In postmenopausal women, hormonal decline changes muscle function and structure. The non-steroidal selective androgen receptor modulators (SARMs) Ostarine (OS) and Ligandrol (LG) have been shown to increase muscle mass and physical function while showing a relative low risk profile. Information about their effects on muscle structure and metabolism is lacking. To analyze this, two experiments were performed using ovariectomized rats as a standard model for postmenopausal conditions. In each experiment, 3-month old Sprague-Dawley rats were divided into five groups (n = 12 to 15). One group remained intact (Non-OVX), the other four groups were ovariectomized (OVX) and remained untreated for eight (OS Experiment) or nine (LG Experiment) weeks. Thereafter, rats of three of the four OVX groups were treated with OS or LG (with doses of 0.04, 0.4, or 4 mg/kg body weight/day) for 5 weeks. Then, uterus, gastrocnemius, and soleus muscles were weighed, fiber size, capillary density, and enzyme activity (lactate dehydrogenase [LDH], citrate synthase [CS], and complex I) were analyzed. In the LG experiment, intramuscular fat content was determined in the quadriceps femoris muscle. All OS treatments resulted in a higher capillary density in the gastrocnemius and longissimus muscles compared with the Non-OVX and the OVX rats, whereas all LG treatments showed a higher capillary density compared with the Non-OVX group. Muscle fiber size and distribution patterns were not changed under either SARM. The CS activity was higher in the longissimus muscle under OS treatment. LG resulted in a higher activity of CS in the gastrocnemius and of LDH in the longissimus muscle. Both SARMs showed an uterotrophic effect, OS at 4 and 0,4 mg dosages, LG at 4 mg dosage. In sum, beneficial effect on muscle vascularization was observed for both SARMs with a stronger impact for OS. LG showed more effect on muscle metabolism. However, a higher muscle weight and intramuscular fat content observed after LG treatment (4 mg) as well as an uterotrophic effect of both SARMs at higher dosages could be considered as an unfavorable side effects and might be a limitation for their application at these dosages.
      View Document Abstract
    • Journal Article

      Critical Care Echocardiography as a Routine Procedure for the Detection and Early Treatment of Cardiac Pathologies 

      Schmidt, Stefan; Dieks, Jana-Katharina; Quintel, Michael; Moerer, Onnen
      Diagnostics 2020; 10(9) p.1-12: Art. 671
      Transthoracic and transesophageal echocardiography are important investigations in the intensive care unit (ICU) to diagnose acute cardiac pathologies and assess the haemodynamic status. Recommendations for critical care echocardiography (CCE) have been published recently, but these still lack an evidence-based foundation. It is not known if performing transthoracic echocardiography (TTE) on a routine basis instead of only when required in acute cases is feasible or clinically useful. In this single-centre prospective observational study, we routinely performed TTE on 111 consecutive non-cardiological, non-cardiothoracic surgical ICU patients in two surgical ICUs in a tertiary care facility. Significant cardiac pathologies were detected in 82 (76.6%) and critical cardiac pathologies in 33 (30.8%) of the 107 patients. The most common critical cardiac pathologies were sPAP > 50 mmHg (19.63%), tricuspid annular plane systolic excursion ≤ 13 mm (9.4%), grade III diastolic dysfunction (8.4%), severe tricuspid valve insufficiency (5.6%) and left ventricular ejection fraction (LV-EF) ˂ 30% (4.7%). Some of the most commonly found cardiac pathologies are not well emphasised in current recommendations and training programs. We observed a progression of the cardiac pathologies previously described in 41 of the patients (91.1%). Patients with echocardiographic abnormalities had a significant survival disadvantage in the ICU. By performing CCE routinely, we observed the range and prevalence of cardiac pathologies that can be detected by echocardiography in critically ill patients. We recommend routine transthoracic CCE in ICU patients for early detection of cardiac pathologies and to help inform early intervention regimens, since cardiac conditions carry a significant survival disadvantage for the ICU patient.
      View Document Abstract
    • Journal Article

      Development and Technical Validation of an Immunoassay for the Detection of APP$_{669–711}$ (Aβ$_{−3–40}$) in Biological Samples 

      Klafki, Hans W.; Rieper, Petra; Matzen, Anja; Zampar, Silvia; Wirths, Oliver; Vogelgsang, Jonathan; Osterloh, Dirk; Rohdenburg, Lara; Oberstein, Timo J.; Jahn, Olaf; et al.
      Beyer, IsaakLachmann, IngolfKnölker, Hans-JoachimWiltfang, Jens
      International Journal of Molecular Sciences 2020; 21(18) p.1-25: Art. 6564
      The ratio of amyloid precursor protein (APP)$_{669–711}$ (Aβ$_{−3–40}$)/Aβ$_{1–42}$ in blood plasma was reported to represent a novel Alzheimer’s disease biomarker. Here, we describe the characterization of two antibodies against the N-terminus of Aβ$_{−3–x}$ and the development and “fit-for-purpose” technical validation of a sandwich immunoassay for the measurement of Aβ$_{−3–40}$. Antibody selectivity was assessed by capillary isoelectric focusing immunoassay, Western blot analysis, and immunohistochemistry. The analytical validation addressed assay range, repeatability, specificity, between-run variability, impact of pre-analytical sample handling procedures, assay interference, and analytical spike recoveries. Blood plasma was analyzed after Aβ immunoprecipitation by a two-step immunoassay procedure. Both monoclonal antibodies detected Aβ$_{−3–40}$ with no appreciable cross reactivity with Aβ$_{1–40}$ or N-terminally truncated Aβ variants. However, the amyloid precursor protein was also recognized. The immunoassay showed high selectivity for Aβ$_{−3–40}$ with a quantitative assay range of 22 pg/mL–7.5 ng/mL. Acceptable intermediate imprecision of the complete two-step immunoassay was reached after normalization. In a small clinical sample, the measured Aβ$_{42}$/Aβ$_{−3–40}$ and Aβ$_{42}$/Aβ$_{40}$ ratios were lower in patients with dementia of the Alzheimer’s type than in other dementias. In summary, the methodological groundwork for further optimization and future studies addressing the Aβ$_{42}$/Aβ$_{−3–40}$ ratio as a novel biomarker candidate for Alzheimer’s disease has been set.
      View Document Abstract
    • Journal Article

      JCSM Rapid Communications: from basic science to clinical research 

      Haehling, Stephan; Ebner, Nicole
      JCSM Rapid Communications 2020; 3(2) p.41-43
      View Document
    • Journal Article

      In vivo Imaging With $^{18}$F-FDG- and $^{18}$F-Florbetaben-PET/MRI Detects Pathological Changes in the Brain of the Commonly Used 5XFAD Mouse Model of Alzheimer's Disease 

      Franke, Timon N.; Irwin, Caroline; Bayer, Thomas A.; Brenner, Winfried; Beindorff, Nicola; Bouter, Caroline; Bouter, Yvonne
      Frontiers in Medicine 2020; 7 p.1-12: Art. 529
      Imaging biomarkers of Alzheimer's disease (AD) that are able to detect molecular changes in vivo and transgenic animal models mimicking AD pathologies are essential for the evaluation of new therapeutic strategies. Positron-emission tomography (PET) using either $^{18}$F-Fluorodeoxyglucose ($^{18}$F-FDG) or amyloid-tracers is a well-established, non-invasive tool in the clinical diagnostics of AD assessing two major pathological hallmarks. $^{18}$F-FDG-PET is able to detect early changes in cerebral glucose metabolism and amyloid-PET shows cerebral amyloid load. However, the suitability of $^{18}$F-FDG- and amyloid-PET in the widely used 5XFAD mouse model of AD is unclear as only a few studies on the use of PET biomarkers are available showing some conflicting results. The aim of this study was the evaluation of $^{18}$F-FDG-PET and amyloid-PET in 5XFAD mice in comparison to neurological deficits and neuropathological changes. Seven- and 12-month-old male 5XFAD mice showed a significant reduction in brain glucose metabolism in $^{18}$F-FDG-PET and amyloid-PET with $^{18}$F-Florbetaben demonstrated an increased cerebral amyloid deposition (n = 4–6 per group). Deficits in spatial reference memory were detected in 12-month-old 5XFAD mice in the Morris Water Maze (n = 10–12 per group). Furthermore, an increased plaque load and gliosis could be proven immunohistochemically in 5XFAD mice (n = 4–6 per group). PET biomarkers $^{18}$F-FDG and $^{18}$F-Florbetaben detected cerebral hypometabolism and increased plaque load even before the onset of severe memory deficits. Therefore, the 5XFAD mouse model of AD is well-suited for in vivo monitoring of AD pathologies and longitudinal testing of new therapeutic approaches.
      View Document Abstract
    • Journal Article

      Long-term opioid therapy for chronic noncancer pain: second update of the German guidelines 

      Petzke, Frank; Bock, Frietjof; Hüppe, Michael; Nothacker, Monika; Norda, Heike; Radbruch, Lukas; Schiltenwolf, Marcus; Schuler, Matthias; Tölle, Thomas; Viniol, Anika; et al.
      Häuser, Winfried
      PAIN Reports 2020; 5(5) p.1-9: Art. e840
      Introduction: The opioid epidemic in North America challenges national guidelines worldwide to define the importance of opioids for the management of chronic noncancer pain (CNCP). Methods: The second update of the German guidelines on long-term opioid therapy for CNCP was developed by 26 scientific associations and 2 patient self-help organizations. A systematic literature search in CENTRAL, Medline, and Scopus (to May 2019) was performed. Meta-analyses of randomized controlled trials and open-label extension studies with opioids for CNCP were conducted. Levels of evidence were assigned according to the Oxford Centre for Evidence-Based Medicine classification system. The formulation and strength of recommendations were established by multistep formalized procedures to reach a consensus according to German Association of the Medical Scientific Societies regulations. The guidelines underwent external review by 4 experts and public commentary. Results: Opioids are one drug-based treatment option for short- (4–12 weeks), intermediate- (13–26 weeks), and long-term (>26 weeks) therapy of chronic pain in osteoarthritis, diabetic polyneuropathy, postherpetic neuralgia, and low back pain. Contraindications are primary headaches, functional somatic syndromes, and mental disorders with the (cardinal) symptom of pain. For specified other clinical pain conditions, short- and long-term therapy with opioids should be evaluated on an individual basis. Long-term therapy with opioids is associated with relevant risks. Conclusion: Responsible application of opioids requires consideration of possible indications and contraindications, as well as regular assessment of clinical response and adverse effects. Neither uncritical opioid prescription nor general rejection of opioids is justified in patients with CNCP.
      View Document Abstract