[Analysis of the prevalence of anticoagulant therapy in patients with cognitive disorders and cerebral amyloid angiopathy (CAA)]. / Analyse zur Häufigkeit einer gerinnungshemmenden Medikation bei Patientinnen mit kognitiven Störungen und zerebraler Amyloidangiopathie (CAA).

OBJECTIVES: To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load. MATERIALS AND METHODS: Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review. RESULTS: Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9 years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. A total of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634). CONCLUSION: CAA is a frequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with a higher number of cortical and subcortical microbleeds.

[Therapeutic effects of complex multimodal rheumatologic treatment in the Rheumatology Center, Rhineland-Palatinate]. / Therapieeffekte der multimodalen rheumatologischen Komplexbehandlung im Rheumazentrum Rheinland-Pfalz.

INTRODUCTION: The concept of complex multimodal rheumatologic treatment (CMRT) has been established for several years in German rheumatologic departments and aims at a multifaceted therapeutic approach to patients with rheumatic diseases. Objective of this study was to examine the therapeutic effect of CMRT in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in an acute rheumatology center. METHODS: The treatment success of CMRT was evaluated by epidemiologic data, patient questionnaires on visual analog scales (VAS) regarding morning stiffness, pain and disease activity (DA), as well as clinical scores (Disease Activity Score 28 [DAS28], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], Bath Ankylosing Spondylitis Functional Index [BASFI]), laboratory inflammation markers (CRP, erythrocyte sedimentation rate) and medication in three visits: visit 1 = begin of CMRT; visit 2 = end of CMRT; visit 3 = 3 months after CMRT. RESULTS: In this study 162 patients from the Rheumatology Center, Rhineland-Palatinate, Germany (96 (59.3%) RA, 30 (18.8%) AS, 36 (22.2%) PsA) were recruited. Statistical examinations revealed a significant improvement of VAS(DA) (visit 2 versus visit 1: RA: p = 0.02, AS: p < 0.001, PsA: p < 0.001), morning stiffness (RA: p < 0.001, AS: p = 0.03, PsA: p < 0.001) and patient reported pain (all; p < 0.001) in the context of CMRT. In the RA and AS subgroups improvements of DAS28 and BASDAI could also be observed (visit 2 versus visit 1: both; p < 0.001). Moreover, significant improvement of patient reported outcomes could be observed 3 months after CMRT regarding VAS(DA) (RA: p = 0.02 und AS: p = 0.03, morning stiffness (PsA: p = 0.02) and patient reported pain (RA: p = 0.01)). Interestingly, subgroup analyses showed that the therapeutic benefit was independent of the concomitant pharmacotherapy. CONCLUSION: The results of this study suggest a therapeutic benefit for patients being treated by CMRT and highlight the high value of this therapeutic concept in patients with systemic-inflammatory rheumatic diseases.

[Organoids for the advancement of intraoperative diagnostic procedures]. / Organoide zur Weiterentwicklung der intraoperativen Diagnostik.

In the context of cancer surgery, there is always a trade-off between oncological safety and preservation of function. This is especially true in pelvic surgery due to the close relationship to the pelvic floor muscles, blood supply and nerves. Currently, risk models, preoperative imaging, the surgeon's assessment, and the intraoperative frozen section serve as the basis for decision-making. New imaging techniques and standardization in frozen section have significantly improved this in recent years. However, limitations remain due to time delays as well as more difficult correct anatomical assignment in the follow-up. Alternative intraoperative techniques may overcome this limitation in the future. Patient-derived organoids have emerged as an important new research vehicle in recent years. They are based on tumor stem cells that, under special culture conditions, form three-dimensional replicas of the original tissue. This makes them ideally suited for testing individual system therapies but also as a validation technique for new intraoperative diagnostic procedures. The Research Training Group 2543/I, which is funded by the German Research Foundation, is researching the potential of new diagnostic methods in an interdisciplinary team regarding validation in addition to intraoperative frozen sections.

Implementation of a clinical guideline to decrease laboratory tests in newborns evaluated for early onset sepsis.

BACKGROUND: Creation of a clinical guideline to reduce the number of complete blood counts (CBCs) obtained on healthy term infants for early onset sepsis (EOS) evaluation secondary to maternal chorioamnionitis. METHODS: A clinical guideline was introduced at four neonatal intensive care units (NICU) to reduce laboratory tests during EOS evaluation. Measures include frequency and timing of CBCs, culture negative sepsis, length of stay, and readmission rate. RESULTS: Mean number of CBCs per patient significantly decreased (2.31±0.62 versus 1.52±0.65) without increasing trends for patients with culture negative sepsis, length of stay, or re-admission. CONCLUSION: The clinical guideline demonstrated a significant reduction in the number of CBCs obtained in well-appearing infants admitted to the NICU secondary to maternal chorioamnionitis.

Are national suicide prevention programs effective? A comparison of 4 verum and 4 control countries over 30 years.

BACKGROUND: Suicide and non-fatal suicidal behavior are significant public health issues worldwide requiring effective preventive interventions. METHODS: The aim of the present study was to analyze the effectiveness of national suicide prevention programs taking a statistical approach involving the segmented regression analysis of interrupted time series data. RESULTS: This study demonstrates that National Suicide Prevention Programs are effective, but this effect seems to correlate with age and sex. Our data have shown a statistical significant decline in suicide rates in the verum countries in males, with the strongest effects in groups aged 25-to-44 years and 45-to-64 years. CONCLUSION: Our study implies that the implementation of a national strategy is an effective tool to reduce suicide rates.

Effect of long term aspirin use on the incidence of prostate cancer: A systematic review and meta-analysis.

BACKGROUND: Previous studies found divergent effects of aspirin use on prostate cancer incidence, potentially due to studies with short durations of aspirin use and insufficient adjustment for screening. METHODS: A systematic review on the association between aspirin use ≥3 years and incident prostate cancer was performed in accordance with the PRISMA and MOOSE criteria. RESULTS: In the cohort studies, aspirin use for at least 3 years was associated with a lower incidence rate of prostate cancer (Odds ratio (OR) 0.88, 95% CI 0.80-0.97). No protective association was established for the case-control studies (OR 0.92, 95% CI 0.68-1.23). Subgroup analysis of advanced and aggressive cancers showed a protective association (OR 0.82, 95% CI 0.71-0.94 and OR 0.75, 95% CI 0.61-0.97). CONCLUSION: This synthesis of observational studies suggests a potential protective association between long term aspirin use and incident prostate cancer. The current literature is highly heterogenous and suffers from inconsistent aspirin dose definition and measurement.

Sleep spindles in bipolar disorder - a comparison to healthy control subjects.

OBJECTIVE: Bipolar disorder is a severe mental disorder for which currently no reliable biomarkers exist. It has been shown that patients with schizophrenia but not with unipolar depression have a reduced density of fast sleep spindles during N2 sleep. The aim of this study was to assess fast sleep spindle density in euthymic patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 24) and healthy control subjects (n = 25) were assessed using all-night polysomnography. Sleep spindles within stage N2 sleep were identified by visual inspection and subdivided into fast (>13 Hz) and slow (≤13 Hz) spindles. All spindles were subsequently characterised by density, frequency, amplitude, duration and coherence. RESULTS: Euthymic patients with bipolar disorder were found to have a reduced density and a lower mean frequency of fast spindles. Slow spindle density and frequency did not differ between groups. There were no differences regarding amplitude, duration or coherence. CONCLUSIONS: A reduction in fast spindle density during N2 sleep points towards thalamic dysfunction as a potential neurobiological mechanism of relevance in bipolar disorder. In addition, a reduced sleep spindle density could be interpreted as a common endophenotype shared with schizophrenia but not unipolar depression and may - if replicated - be of utility in early recognition and risk stratification.

Reviewing the current evidence supporting early B-cells as the cellular origin of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly malignant skin cancer characterized by early metastases and poor survival. Although MCC is a rare malignancy, its incidence is rapidly increasing in the U.S. and Europe. The discovery of the Merkel cell polyomavirus (MCPyV) has enormously impacted our understanding of its etiopathogenesis and biology. MCCs are characterized by trilinear differentiation, comprising the expression of neuroendocrine, epithelial and B-lymphoid lineage markers. To date, it is generally accepted that the initial assumption of MCC originating from Merkel cells (MCs) is unlikely. This is owed to their post-mitotic character, absence of MCPyV in MCs and discrepant protein expression pattern in comparison to MCC. Evidence from mouse models suggests that epidermal/dermal stem cells might be of cellular origin in MCC. The recently formulated hypothesis of MCC originating from early B-cells is based on morphology, the consistent expression of early B-cell lineage markers and the finding of clonal immunoglobulin chain rearrangement in MCC cells. In this review we elaborate on the cellular ancestry of MCC, the identification of which could pave the way for novel and more effective therapeutic regimens.

[Merkel cell carcinoma: cutaneous manifestation of a highly malignant pre-/pro-B cell neoplasia? : Novel concept about the cellular origin of Merkel cell carcinoma]. / Merkelzellkarzinom: kutane Manifestation einer hochmalignen Prä-/pro-B-Zell-Neoplasie? : Neues Konzept zum zellulären Ursprung des Merkelzellkarzinoms.

Merkel cell carcinoma (MCC) is a relatively rare but highly malignant non-melanoma skin cancer of the elderly and immunosuppressed patients. The discovery of the Merkel cell polyomavirus (MCPyV) in 2008 significantly impacted the understanding of the etiopathogenesis of MCC. MCPyV is clonally integrated into the MCC genome and approximately 80% of MCC are MCPyV-positive. Recent results of clinical trials using blockade of the PD-1 immune modulatory pathway are promising for the future treatment of MCC. Despite this major progress of the past few years, the cellular origin of MCC still remains obscure. Based on histomorphology, gene expression profiling, and molecular analyses, we have recently hypothesized that MCC originates from pre­/pro-B cells. Here we review putative cells of MCC, including Merkel cells, (epi­)dermal stem cells, and pro­/pre-B cells. In the present work, the focus is on the concept of pre­/pro-B cells as the cellular origin of MCC, which might also impact the understanding of other human small cell malignancies of unknown cellular origin, such as small cell carcinomas of the lung and other anatomical locations. In addition, this concept might pave the way for novel treatment options, especially for advanced MCC.

Quantitative Macroscopic Anatomy of the Giraffe (Giraffa camelopardalis) Digestive Tract.

Quantitative data on digestive anatomy of the world's largest ruminant, the giraffe, are scarce. Data were collected from a total of 25 wild-caught and 13 zoo-housed giraffes. Anatomical measures were quantified by dimension, area or weight and analysed by allometric regression. The majority of measures scaled positively and isometrically to body mass. Giraffes had lower tissue weight of all stomach compartments and longer large intestinal length than cattle. When compared to other ruminants, the giraffe digestive tract showed many of the convergent morphological adaptations attributed to browsing ruminants, for example lower reticular crests, thinner ruminal pillars and smaller surface area of the omasal laminae. Salivary gland weight of the giraffe, however, resembled that of grazing ruminants. This matches a previous finding of similarly small salivary glands in the other extant giraffid, the okapi (Okapia johnstoni), suggesting that not all convergent characteristics need be expressed in all species and that morphological variation between species is a combination of phylogenetic and adaptational signals.

Complete determination of molecular orbitals by measurement of phase symmetry and electron density.

Several experimental methods allow measuring the spatial probability density of electrons in atoms, molecules and solids, that is, the absolute square of the respective single-particle wave function. But it is an intrinsic problem of the measurement process that the information about the phase is generally lost during the experiment. The symmetry of this phase, however, is a crucial parameter for the knowledge of the full orbital information in real space. Here, we report on a key experiment that demonstrates that the phase symmetry can be derived from a strictly experimental approach from the circular dichroism in the angular distribution of photoelectrons. In combination with the electron density derived from the same experiment, the full quantum mechanical wave function can thus be determined experimentally.

Core hole-electron correlation in coherently coupled molecules.

We study the core hole-electron correlation in coherently coupled molecules by energy dispersive near edge x-ray absorption fine-structure spectroscopy. In a transient phase, which exists during the transition between two bulk arrangements, 1,4,5,8-naphthalene-tetracarboxylicacid-dianhydride multilayer films exhibit peculiar changes of the line shape and energy position of the x-ray absorption signal at the C K-edge with respect to the bulk and gas phase spectra. By a comparison to a theoretical model based on a coupling of transition dipoles, which is established for optical absorption, we demonstrate that the observed spectroscopic differences can be explained by an intermolecular delocalized core hole-electron pair. By applying this model we can furthermore quantify the coherence length of the delocalized core exciton.

Studies on the emission behavior of polypropylene by gas chromatography/mass spectrometry with static headspace or thermodesorption.

Emissions from polypropylene (PP) may cause undesired smell, be harmful, or lead to so-called fogging which prohibits its use for car interiors. Thus, qualitative as well as quantitative emission studies are necessary. Thermodesorption (TDS) and static headspace (sHS) with subsequent GC-MS analysis are two powerful tools for analyzing the emission behavior of polymers with a minimum of sample handling. In this work we investigated the emission behavior of PP with TDS and sHS coupled to GC-MS paying special attention to quantitative considerations and to the relevance of emitted substances for fogging phenomena. After extraction for 30min and incubation for 2h, TDS-GC-MS and sHS-GC-MS results were satisfyingly repeatable (with relative standard deviations up to 5%). TDS allowed to introduce substances up to higher boiling points into the GC-MS system, but required to control sample geometry, as emission depended rather on sample surface than on sample mass. In sHS, emission was governed by partitioning between the gas and the sample phase rather than by full evaporation of the analytes. Above a certain analyte-dependent amount, peak area became independent of the sample amount. However, if the sample amount was kept constant, peak areas of emitted substances showed a linear dependence upon concentration of volatiles. Therefore, accurate quantitation was still possible. Typically alkanes, alkenes and dialkenes dominate TDS-GC-MS and sHS-GC-MS chromatograms of PP. They only contributed to fogging if they had a chain length higher than C16. These substances were only detectable when TDS was used for sample introduction, but not with sHS. sHS-GC-MS is thus not useful for judging fogging behavior.

Human milk macronutrient analysis using point-of-care near-infrared spectrophotometry.

OBJECTIVE: To demonstrate that the real-time nutritional analysis of human milk carbohydrate, fat and protein with near-infrared (NIR) spectrophotometric methods is accurate. STUDY DESIGN: A prospective study of the measurement of the macronutrient content of human milk. Milk was first analyzed on the SpectraStar 2400 Near Infrared Analyzer (Unity Scientific, Columbia, MD, USA), and then sent for primary chemical analysis for fat, protein and carbohydrate. Forty-two samples were used to create a calibration file. Ten samples were then used to validate the machine. RESULT: After logistic regression analysis, the validation set had a correlation (r (2)) of 0.91 for carbohydrates, 0.95 for fat and 0.95 for protein. CONCLUSION: This study demonstrates the feasibility of the use of NIR for nutrient analysis of human milk. NIR offers the potential for analysis and adjustable fortification of human milk to optimize nutrient intake for the high-risk neonate.

Sunitinib in metastatic thymic carcinomas: laboratory findings and initial clinical experience.

BACKGROUND: Thymic carcinoma (TC) is a rare aggressive tumour. Median survival with current treatments is only 2 years. Sunitinib is a multi-targeted tyrosine kinase inhibitor that has shown benefit in various other cancers. METHODS: Laboratory analyses of snap-frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases (RTKs) in TC samples. On the basis of molecular analyses showing activation of multiple RTKs in their tumour, four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols. RESULTS: RTK analysis in three of the patients showed activation of multiple RTKs, including platelet-derived growth factor-beta and vascular endothelial growth factor 3. Mutations of EGFR, c-KIT, KRAS, and BRAF genes were not found. Administration of sunitinib yielded a partial remission (lasting 2 to 18+ months) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in 18F-FDG-PET in another one. The overall survival with sunitinib treatment ranges from 4 to 40+ months. Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re-administration of sunitinib. CONCLUSIONS: Sunitinib is an active treatment for metastatic TC. A panel of molecular analyses may be warranted for optimal patient selection.

Neuronal correlates of affective theory of mind in schizophrenia out-patients: evidence for a baseline deficit.

BACKGROUND: Schizophrenia out-patients have deficits in affective theory of mind (ToM) but also on more basal levels of social cognition, such as the processing of neutral and emotional expressions. These deficits are associated with changes in brain activation in the amygdala and the superior temporal sulcus (STS). However, until now there have been no studies that examined these different levels of social cognition and their neurobiological underpinnings in patients within one design. METHOD: Sixteen medicated schizophrenia out-patients and 16 matched healthy controls were studied with functional magnetic resonance imaging (fMRI) during a social cognition task that allows the investigation of affective ToM (aToM), emotion recognition and the processing of neutral facial expressions. RESULTS: Patients showed a deficit in emotion recognition and a more prominent deficit in aToM. The performance in aToM and in emotion recognition was correlated in the control group but not in the schizophrenia group. Region-of-interest analysis of functional brain imaging data revealed no difference between groups during aToM, but a hyperactivation in the schizophrenia group in the left amygdala and right STS during emotion recognition and the processing of neutral facial expressions. CONCLUSIONS: The results indicate that schizophrenia out-patients have deficits at several levels of social cognition and provide the first evidence that deficits on higher-order social cognitive processes in schizophrenia may be traced back to an aberrant processing of faces per se.

Genotoxic effect of polycyclic aromatic hydrocarbons in the metropolitan area of Porto Alegre, Brazil, evaluated by Helix aspersa (Müller, 1774).

The purpose of this study was to biomonitor metropolitan areas of Porto Alegre (Brazil) for PAHs associated with atmospheric particles and check their effects on the DNA of the land mollusk Helix aspersa. The sampling sites are located in an urban area with heavy traffic: (i) Canoas, (ii) Sapucaia do Sul, and (iii) FIERGS/Porto Alegre. The samples were collected during a continuous period of 24 hours during 15 days using Stacked Filter Units (SFU) on polycarbonate filters (two separated size fractions: PM(10-2.5) and PM(< 2.5)). The concentrations of 16 major PAHs were determined according to EPA. Comet assay on H. aspersa hemolymph cells was chosen for genotoxicity evaluation. This evaluation shows that, in general, the smaller PM-size fractions (PM(< 2.5)) have the highest genotoxicity and contain higher concentrations of extractable organic matter. In addition, associations between chemical characteristics and PM carcinogenicity tend to be stronger for the smaller PM-size fractions.

P2 receptor-mediated stimulation of the PI3-K/Akt-pathway in vivo.

ATP acts as a growth factor as well as a toxic agent by stimulating P2 receptors. The P2 receptor-activated signaling cascades mediating cellular growth and cell survival after injury are only incompletely understood. Therefore, the aim of the present study was to identify the role of the phosphoinositide 3 kinase (PI3-K/Akt) and the mitogen-activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) pathways in P2Y receptor-mediated astrogliosis after traumatic injury and after microinfusion of ADP beta S (P2Y(1,12,13) receptor agonist) into the rat nucleus accumbens (NAc). Mechanical damage and even more the concomitant treatment with ADP beta S, enhanced P2Y(1) receptor-expression in the NAc, which could be reduced by pretreatment with the P2X/Y receptor antagonist PPADS. Quantitative Western blot analysis indicated a significant increase in phosphorylated (p)Akt and pERK1/2 2 h after ADP beta S-microinjection. Pretreatment with PPADS or wortmannin abolished the up-regulation of pAkt by injury alone or ADP beta S-treatment. The ADP beta S-enhanced expression of the early apoptosis marker active caspase 3 was reduced by PPADS and PD98059, but not by wortmannin. Multiple immunofluorescence labeling indicated a time-dependent expression of pAkt and pMAPK on astrocytes and neurons and additionally the colocalization of pAkt, pMAPK, and active caspase 3 with the P2Y(1) receptor especially at astrocytes. In conclusion, the data show for the first time the involvement of PI3-K/Akt-pathway in processes of injury-induced astroglial proliferation and anti-apoptosis via activation of P2Y(1) receptors in vivo, suggesting specific roles of P2 receptors in glial cell pathophysiology in neurodegenerative diseases.

Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways.

Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-kappaB and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFbeta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent beta-catenin was monitored in response to the inhibition of GSK3beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFbeta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.