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    Circulating miRNAs as Diagnostic Biomarkers for Parkinson’s Disease 

    Roser, Anna Elisa; Caldi Gomes, Lucas; Schünemann, Jonas; Maass, Fabian; Lingor, Paul
    Frontiers in Neuroscience 2018; 12: Art. 625
    Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. Its main neuropathological hallmarks are the degeneration of dopaminergic neurons in the substantia nigra and alpha-synuclein containing protein inclusions, called Lewy Bodies. The diagnosis of idiopathic PD is still based on the assessment of clinical criteria, leading to an insufficient diagnostic accuracy. Additionally, there is no biomarker available allowing the prediction of the disease course or monitoring the response to therapeutic approaches. So far, protein biomarker candidates such as alpha-synuclein have failed to improve diagnosis of PD. Circulating microRNAs (miRNAs) in body fluids are promising biomarker candidates for PD, as they are easily accessible by nonor minimally-invasive procedures and changes in their expression are associated with pathophysiological processes relevant for PD. Advances in miRNA analysis methods resulted in numerous recent publications on miRNAs as putative biomarkers. Here, we discuss the applicability of different body fluids as sources for miRNA biomarkers, highlight technical aspects of miRNA analysis and give an overview on published studies investigating circulating miRNAs as biomarker candidates for diagnosis of PD and other Parkinsonian syndromes.
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    Risk and Outcome after Simultaneous Carotid Surgery and Cardiac Surgery: Single Centre Experience 

    Tirilomis, Theodor; Zenker, Dieter; Stojanovic, Tomislav; Malliarou, Stella; Schoendube, Friedrich A.
    International Journal of Vascular Medicine 2018; 2018 p.1-5: Art. 7205903
    of the study was the analysis of risks and outcome after simultaneous carotid and cardiac surgery. Methods. We retrospectively reviewed the medical records of 100 consecutive patients who underwent simultaneous carotid surgery and open-heart surgery during a 5-year period (from 2006 to 2010). Seventy patients were male and 30 female; the mean age was 70.9±7.9 years (median: 71.8 years). Seventy-three patients underwent coronary bypass grafting (CABG), 18 patients combined CABGand valve procedures, 7 patients CABG combined with other procedures, and 3 patients isolated valve surgery.More than half of patients had had bilateral carotid artery pathology (n=51) including contralateral carotid artery occlusion in 12 cases. Results. Carotid artery patch plasty was performed in 71 patients and eversion technique in 29. In 75 cases an intraluminal shunt was used.Thirty-day mortality rate was 7% due to cardiac complications (n=5), metabolic disturbance (n=1), and diffuse cerebral embolism (n=1). There were no carotid surgery-related deaths. Postoperatively, transient cerebral ischemia occurred in one patient and stroke withmild permanent neurological deficit (Rankin level 2) in another patient. Conclusion. Simultaneous carotid artery surgery and open-heart surgery have low risk. The underlying cardiac disease influences outcome.
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    Effects of RANKL Knockdown by Virus-like Particle-Mediated RNAi in a Rat Model of Osteoporosis 

    Hoffmann, Daniel B.; Gruber, Jens; Böker, Kai O.; Deppe, Delia; Sehmisch, Stephan; Schilling, Arndt F.; Lemus-Diaz, Nicolas; Komrakova, Marina; Schneider, Stefan
    Molecular Therapy - Nucleic Acids 2018; 12 p.443-452
    Rebalancing of the RANKL/OPG system seems to be an effective treatment strategy in postmenopausal osteoporosis. Here, we evaluate the knockdown of RANKL by in-vivo-delivered siRNA in a rat model of osteoporosis. Virus-like-particles (VLPs) derived from polyoma JC virus were used for delivering RANKL siRNA in ovariectomized (OVX) rats. 48 rats were ovariectomized and treated with either 17β-estradiol (E2), VLPs containing RANKL siRNA (siRANKL), or VLPs containing non-cognate siRNA (siCtrl). All OVX groups were subdivided into the prophylaxis group (PG) and the therapy group (TG). The PG received treatment directly after being OVX for 10 weeks. The TG received treatment 5 weeks after being OVX for 5 weeks. Rats were sacrificed 10 weeks after being OVX. Bone and blood samples were analyzed. E2 and siRANKL showed a significant knockdown of RANKL mRNA. A protein knockdown was observed with E2 and siRANKL in the TG but not in the PG. No distinct improvements in biomechanical and morphological properties of the bones were observed after siRANKL treatment. In the PG, E2 protected the bone structure. We demonstrated successful mRNA and protein knockdown by VLP-mediated RNAi in vivo. Knockdown of membranous RANKL did not result in significant improvements of bone properties in this model of early-stage postmenopausal osteoporosis.
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    Heterologous expression and enhanced production of β-1,4-glucanase of Bacillus halodurans C-125 in Escherichia coli 

    Zeeshan, Nadia; Naz, Saher; Naz, Shumaila; Afroz, Amber; Zahur, Muzna; Zia, Safia
    Electronic Journal of Biotechnology 2018; 34 p.29-36
    insubstantial amount for industrial applications. Endo-1, 4-β-glucanases (Egl) is one of the major enzyme involved in degradation of cellulose, an important component of plant cell wall. The present study was aimed at enhancing the production of endo-1, 4-β-glucanases (Egl) of Bacillus halodurans in Escherichia coli. Results: A putative Egl gene of Bacillus Halodurans was expressed in E. coli by cloning in pET 22b (+).On induction with isopropyl-b-D-1-thiogalactopyranoside, the enzyme expression reached upto ~20% of the cell protein producing 29.2 mg/liter culture. An increase in cell density to 12 in auto-inducing LB medium (absorbance at 600 nm) enhanced β-glucanase production up to 5.4 fold. The molecular mass of the enzyme was determined to be 39 KDa, which is nearly the same as the calculated value. Protein sequence was analyzed by CDD, Pfam, I TASSER, COACH, PROCHECK Servers and putative amino acids involved in the formation of catalytic, substrate and metal binding domains were identified. Phylogenetic analysis of the β-glucanases of B. halodurans was performed and position of Egl among other members of the genus Bacillus producing endo-glucanases was determined. Temperature and pH optima of the enzyme were found to be 60°C and 8.0, respectively, under the assay conditions. Conclusion: Production of endo-1, 4 β-glucanase enzymes fromB. halodurans increased several foldswhen cloned in pET vector and expressed in E. coli. To our knowledge, this is the first report of high-level expression and characterization of an endo-1, 4 β-glucanases from B. halodurans
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    PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations 

    Blesinger, Hannah; Kaulfuß, Silke; Aung, Thiha; Schwoch, Sonja; Prantl, Lukas; Rößler, Jochen; Wilting, Jörg; Becker, Jürgen
    PLOS ONE 2018; 13(7): Art. e0200343
    Lymphatic malformations (LM) are characterized by the overgrowth of lymphatic vessels during pre- and postnatal development. Macrocystic, microcystic and combined forms of LM are known. The cysts are lined by lymphatic endothelial cells (LECs). Resection and sclerotherapy are the most common treatment methods. Recent studies performed on LM specimens in the United States of America have identified activating mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene in LM. However, whole tissue but not isolated cell types were studied. Here, we studied LM tissues resected at the University Hospitals Freiburg and Regensburg, Germany. We isolated LECs and fibroblasts separately, and sequenced the commonly affected exons 8, 10, and 21 of the PIK3CA gene. We confirm typical monoallelic mutations in 4 out of 6 LM-derived LEC lines, and describe two new mutations i.) in exon 10 (c.1636C>A; p.Gln546Lys), and ii.) a 3bp in-frame deletion of GAA (Glu109del). LM-derived fibroblasts did not possess such mutations, showing cell-type specificity of the gene defect. High activity of the PIK3CA-AKT- mTOR pathway was demonstrated by hyperphosphorylation of AKT-Ser473 in all LM-derived LECs (including the ones with newly identified mutations), as compared to normal LECs. Additionally, hyperphosphorylation of ERK was seen in all LM-derived LECs, except for the one with Glu109del. In vitro, the small molecule kinase inhibitors Buparlisib/BKM-120, Wortmannin, and Ly294002, (all inhibitors of PIK3CA), CAL-101 (inhibitor of PIK3CD), MK-2206 (AKT inhibitor), Sorafenib (multiple kinases inhibitor), and rapamycin (mTOR inhibitor) significantly blocked proliferation of LM-derived LECs in a concentration-dependent manner, but also blocked proliferation of normal LECs. However, MK-2206 appeared to be more specific for mutated LECs, except in case of Glu109 deletion. In sum, children that are, or will be, treated with kinase inhibitors must be monitored closely.
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    Prevalence and Strain Characterization of Clostridioides (Clostridium) difficile in Representative Regions of Germany, Ghana, Tanzania and Indonesia - A Comparative Multi-Center Cross-Sectional Study 

    Seugendo, Mwanaisha; Janssen, Iryna; Lang, Vanessa; Hasibuan, Irene; Bohne, Wolfgang; Cooper, Paul; Daniel, Rolf; Gunka, Katrin; Kusumawati, R. L.; Mshana, Stephen E.; et al.
    von Müller, LutzOkamo, BenardOrtlepp, Jan R.Overmann, JörgRiedel, ThomasRupnik, MajaZimmermann, OrtrudGroß, Uwe
    Frontiers in Microbiology 2018; 9: Art. 1843
    Clostridioides (Clostridium) difficile infections (CDI) are considered worldwide as emerging health threat. Uptake of C. difficile spores may result in asymptomatic carrier status or lead to CDI that could range from mild diarrhea, eventually developing into pseudomembranous colitis up to a toxic megacolon that often results in high mortality. Most epidemiological studies to date have been performed in middle- and high income countries. Beside others, the use of antibiotics and the composition of the microbiome have been identified as major risk factors for the development of CDI. We therefore postulate that prevalence rates of CDI and the distribution of C. difficile strains differ between geographical regions depending on the regional use of antibiotics and food habits. A total of 593 healthy control individuals and 608 patients suffering from diarrhea in communities in Germany, Ghana, Tanzania and Indonesia were selected for a comparative multi-center cross-sectional study. The study populations were screened for the presence of C. difficile in stool samples. Cultured C. difficile strains (n = 84) were further subtyped and characterized using PCR-ribotyping, determination of toxin production, and antibiotic susceptibility testing. Prevalence rates of C. difficile varied widely between the countries. Whereas high prevalence rates were observed in symptomatic patients living in Germany and Indonesia (24.0 and 14.7%), patients from Ghana and Tanzania showed low detection rates (4.5 and 6.4%). Differences were also obvious for ribotype distribution and toxin repertoires. Toxin A+/B+ ribotypes 001/072 and 078 predominated in Germany, whereas most strains isolated from Indonesian patients belonged to toxin A+/B+ ribotype SLO160 and toxin A-/B+ ribotype 017. With 42.9-73.3%, non-toxigenic strains were most abundant in Africa, but were also found in Indonesia at a rate of 18.2%. All isolates were susceptible to vancomycin and metronidazole. Mirroring the antibiotic use, however, moxifloxacin resistance was absent in African C. difficile isolates but present in Indonesian (24.2%) and German ones (65.5%). This study showed that CDI is a global health threat with geographically different prevalence rates which might reflect distinct use of antibiotics. Significant differences for distributions of ribotypes, toxin production, and antibiotic susceptibilities were observed.
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    Cortical representation of auricular muscles in humans: A robot-controlled TMS mapping and fMRI study 

    Meincke, Jonna; Hewitt, Manuel; Reischl, Markus; Rupp, Rüdiger; Schmidt-Samoa, Carsten; Liebetanz, David
    PLOS ONE 2018; 13(7): Art. e0201277
    BACKGROUND: Most humans have the ability to activate the auricular muscles. Although (intentional) control suggests an involvement of higher cortical centers underlying posterior auricular muscle (PAM) activation, the cortical representation of the auricular muscles is still unknown. METHODS: With the purpose of identifying a possible cortical representation area we performed automated robotic and image-guided transcranial magnetic stimulation (TMS) mapping (n = 8) and functional magnetic resonance imaging (fMRI) (n = 13). For topographical comparison, a similar experimental protocol was applied for the first dorsal interosseus muscle (FDI) of the hand. RESULTS: The calculated centers of gravity (COGs) of both muscles were located on the precentral gyrus with the PAM COGs located more laterally compared to the FDI. The distance between the mean PAM and mean FDI COG was 26.3 mm. The TMS mapping results were confirmed by fMRI, which showed a dominance of cortical activation within the precentral gyrus during the corresponding motor tasks. The correspondence of TMS and fMRI results was high. CONCLUSION: The involvement of the primary motor cortex in PAM activation might point to an evolved function of the auricular muscles in humans and/or the ability of intentional (and selective) muscle activation.
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    Mutational Landscapes and Phenotypic Spectrum of SWI/SNF-Related Intellectual Disability Disorders 

    Bögershausen, Nina; Wollnik, Bernd
    Frontiers in Molecular Neuroscience 2018; 11: Art. 252
    Mutations in genes that encode proteins of the SWI/SNF complex, called BAF complex in mammals, cause a spectrum of disorders that ranges from syndromic intellectual disability to Coffin-Siris syndrome (CSS) to Nicolaides-Baraitser syndrome (NCBRS). While NCBRS is known to be a recognizable and restricted phenotype, caused by missense mutations in SMARCA2, the term CSS has been used lately for a more heterogeneous group of phenotypes that are caused by mutations in either of the genes ARID1B, ARID1A, ARID2, SMARCA4, SMARCB1, SMARCE1, SOX11, or DPF2. In this review, we summarize the current knowledge on the phenotypic traits and molecular causes of the above named conditions, consider the question whether a clinical distinction of the phenotypes is still adequate, and suggest the term "SWI/SNF-related intellectual disability disorders" (SSRIDDs). We will also outline important features to identify the ARID1B-related phenotype in the absence of classic CSS features, and discuss distinctive and overlapping features of the SSRIDD subtypes. Moreover, we will briefly review the function of the SWI/SNF complex in development and describe the mutational landscapes of the genes involved in SSRIDD.
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    Mooney face stimuli for visual perception research 

    Schwiedrzik, Caspar M; Melloni, Lucia; Schurger, Aaron
    PLOS ONE 2018; 13(7): Art. e0200106
    In 1957, Craig Mooney published a set of human face stimuli to study perceptual closure: the formation of a coherent percept on the basis of minimal visual information. Images of this type, now known as "Mooney faces", are widely used in cognitive psychology and neuroscience because they offer a means of inducing variable perception with constant visuo-spatial characteristics (they are often not perceived as faces if viewed upside down). Mooney's original set of 40 stimuli has been employed in several studies. However, it is often necessary to use a much larger stimulus set. We created a new set of over 500 Mooney faces and tested them on a cohort of human observers. We present the results of our tests here, and make the stimuli freely available via the internet. Our test results can be used to select subsets of the stimuli that are most suited for a given experimental purpose.
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    Prehospital ultrasound-guided nerve blocks improve reduction-feasibility of dislocated extremity injuries compared to systemic analgesia. A randomized controlled trial 

    Büttner, Benedikt; Mansur, Ashham; Kalmbach, Matthias; Hinz, José; Volk, Thomas; Szalai, Karoly; Roessler, Markus; Bergmann, Ingo
    PLOS ONE 2018; 13(7): Art. e0199776
    BACKGROUND: Out-of-hospital analgosedation in trauma patients is challenging for emergency physicians due to associated complications. We compared peripheral nerve block (PNB) with analgosedation (AS) as an analgetic approach for patients with isolated extremity injury, assuming that prehospital required medical interventions (e.g. reduction, splinting of dislocation injury) using PNB are less painful and more feasible compared to AS. METHODS: Thirty patients (aged 18 or older) were randomized to receive either ultrasound-guided PNB (10 mL prilocaine 1%, 10 mL ropivacaine 0.2%) or analgosedation (midazolam combined with s-ketamine or with fentanyl). Reduction-feasibility was classified (easy, intermediate, impossible) and pain scores were assessed using numeric rating scales (NRS 0-10). RESULTS: Eighteen patients were included in the PNB-group and twelve in the AS-group; 15 and 9 patients, respectively, suffered dislocation injury. In the PNB-group, reduction was more feasible (easy: 80.0%, impossible: 20.0%) compared to the AS-group (easy: 22.2%, intermediate: 22.2%, impossible: 55.6%; p = 0.01). During medical interventions, 5.6% [1/18] of the PNB-patients and 58.3% [7/12] of the AS-patients experienced pain (p<0.01). Recorded pain scores were significantly lower in the PNB-group during prehospital medical intervention (median[IQR] NRS PNB: 0[0-0]) compared to the AS-group (6[0-8]; p<0.001) as well as on first day post presentation (NRS PNB: 1[0-5], AS: 5[5-7]; p = 0.050). All patients of the PNB-group would recommend their analgesic technique (AS: 50.0%, p<0.01). CONCLUSIONS: Prehospital ultrasound-guided PNB is rapidly performed in extremity injuries with high success. Compared to the commonly used AS in trauma patients, PNB significantly reduces pain intensity and severity.
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    Hemodiafiltration Treatment for Severe Valproic Acid Intoxication: Case Report and Updated Systematic Literature Review 

    Tichelbäcker, Tobias; Herath, Judith; Tampe, Björn; Korsten, Peter
    Frontiers in Medicine 2018; 5: Art. 224
    Background: Valproic acid (VPA) has been approved for the treatment of seizure disorders. It is also commonly used in psychiatric disorders, such as schizophrenia spectrum disorders. With increasing administration, reports of intoxications are more frequently reported. The most common findings of VPA intoxication are central nervous system depression, respiratory depression, hypotension, metabolic acidosis, and elevated lactate, among others. Methods: We describe a case report of VPA intoxication with hemodiafiltration (HDF) as extracorporeal treatment (ECTR) for removal of VPA. This treatment modality has only rarely been reported in the current literature. In addition, we performed an updated systematic literature review (SLR) of additional cases on the topic ranging fromDecember 1st, 2014 to April 20th, 2018. We searched MEDLINE and Web of Science for relevant references. Results: In the presented case, VPA intoxication occurred in a 46-year-old female patient after oral ingestion of 56 g of VPA. In addition to vasopressors and endotracheal intubation, we administered L-Carnitine (L-Car) and performed hemodiafiltration treatment. After intravenous therapy with L-Car and simultaneous HDF sessions, we observed full recovery without neurological sequelae. The SLR identified 8 additional articles reporting favorable outcomes with extracorporeal treatments in most cases. Conclusion: HDF and other extracorporeal procedures are safe and effective therapeutic options in patients with VPA intoxication. The choice of ECTR modalitymainly depends on local experience and the setting. In the present case, ingestion of 56 g was successfully treated with HDF. These findings are in line with several other case reports describing positive outcomes. Extracorporeal treatment, including HDF, should be considered early in the management of VPA intoxication. Supporting evidence is emerging, but it is of limited quality.
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    Crohn's disease patient serum changes protein expression in a human mesenchymal stem cell model in a linear relationship to patients' disease stage and to bone mineral density 

    Blaschke, Martina; Koepp, Regine; Lenz, Christof; Kruppa, Jochen; Jung, Klaus; Siggelkow, Heide
    Journal of Clinical & Translational Endocrinology 2018; 13 p.26-38
    Background: Crohn's disease (CD) is associated with a higher prevalence of osteoporosis, a complication that is recognized as a significant cause of morbidity. Its pathogenesis is controversial, but the activity of CD is one contributing factor. Methods: We stimulated SCP-1 cells (mesenchymal stem cell line) under osteogenic conditions with serum from adult patients with CD in the symptomatic phase (SP) and in remission (R) and with control sera. Concentrations of IL-6, IL-1 beta, and TNF alpha in the sera were measured. Patients were classified as normal or osteopenic/osteoporotic based on bone mineral density (BMD) T-score measurements. After 14 days in culture, protein expression and gene ontology (GO) annotation analysis was performed. Results: Cytokine concentrations (IL-6, IL-1 beta, TNF alpha) varied within sera groups. None of the cytokines were significantly increased in the symptomatic phase compared to remission. Protein analysis revealed 17 proteins regulated by the SP versus R phase sera of disease. A linear relationship between CDAI (Crohn's disease activity index) and normalized protein expression of APOA1 and 2, TTR, CDKAL1 and TUBB6 could be determined. Eleven proteins were found to be differentially regulated comparing osteoporosis-positive and osteoporosis-negative sera. Gene annotation and further analysis identified these genes as part of heme and erythrocyte metabolism, as well as involved in hypoxia and in endocytosis. A significant linear relationship between bone mineral density and normalized protein expression could be determined for proteins FABP3 and TTR. Conclusion: Our explorative results confirm our hypothesis that factors in serum from patients with CD change the protein expression pattern of human immortalized osteoblast like cells. We suggest, that these short time changes indeed influence factors of bone metabolism.
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    Postoperative long-term results for the comparison of the symmetry of the upper lip during lip closure according to Millard and Pfeifer 

    Kauffmann, Philipp; Cordesmeyer, Robert; Fouellefack, Giséle Awondzeko; Schminke, Boris; Wiese, Karl-Günther
    Maxillofacial Plastic and Reconstructive Surgery 2018; 40(1): Art. 18
    Background: Clefts in newborns are associated with severe morphological and functional impairment. Especially the lip is of importance as if the treatment result is unsatisfactory, it can lead to psychological changes in the patient. Different operative procedures have been developed over the last decades. The aim of the presented study was the comparison of the surgical techniques according to Millard and Pfeifer regarding the temporal development of the postoperative symmetry of the lip height and mouth width. Methods: Digitized photographs of patients from the department of oral and maxillofacial surgery at the University of Göttingen were evaluated from 1979 to 1996. With a video analysis program, the lip height and mouth width were analyzed regarding the symmetry. We demonstrated the symmetry values over a period of 8 years in order to show the influence of growth on postoperative results. Results: The development of the vertical symmetry of the Philtrum and the lip vermillion on the cleft side in comparison to the healthy side behaves differently depending on Pfeifer and Millard. The lip height of the cleft lip was shorter in both techniques than on the healthy side, but Pfeifer's difference was significantly more pronounced. The lip vermillion height on the cleft side was slightly shorter in the Millard group and markedly larger in the Pfeifer group. Both techniques can achieve good symmetry results for the vertical dimension of the lip. According to Pfeifer, the development of the horizontal dimension on the cleft side is bigger within the first 4 years than on the healthy side; according to the Millard technique, the horizontal development is smaller. These differences are greater within the first 6 years and approach between the 6th and 8th year. Conclusions: The Millard technique demonstrates better results concerning the philtrum and vermillion symmetry during growth within the first 6 years. Over the whole study period, growth corrects the philtrum and vermillion symmetry within the Pfeifer group.
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    A comparative study of RNA-Seq and microarray data analysis on the two examples of rectal-cancer patients and Burkitt Lymphoma cells. 

    Wolff, Alexander; Bayerlová, Michaela; Gaedcke, Jochen; Kube, Dieter; Beißbarth, Tim
    PLOS ONE 2018; 13(5): Art. e0197162
    BACKGROUND: Pipeline comparisons for gene expression data are highly valuable for applied real data analyses, as they enable the selection of suitable analysis strategies for the dataset at hand. Such pipelines for RNA-Seq data should include mapping of reads, counting and differential gene expression analysis or preprocessing, normalization and differential gene expression in case of microarray analysis, in order to give a global insight into pipeline performances. METHODS: Four commonly used RNA-Seq pipelines (STAR/HTSeq-Count/edgeR, STAR/RSEM/edgeR, Sailfish/edgeR, TopHat2/Cufflinks/CuffDiff)) were investigated on multiple levels (alignment and counting) and cross-compared with the microarray counterpart on the level of gene expression and gene ontology enrichment. For these comparisons we generated two matched microarray and RNA-Seq datasets: Burkitt Lymphoma cell line data and rectal cancer patient data. RESULTS: The overall mapping rate of STAR was 98.98% for the cell line dataset and 98.49% for the patient dataset. Tophat's overall mapping rate was 97.02% and 96.73%, respectively, while Sailfish had only an overall mapping rate of 84.81% and 54.44%. The correlation of gene expression in microarray and RNA-Seq data was moderately worse for the patient dataset (ρ = 0.67-0.69) than for the cell line dataset (ρ = 0.87-0.88). An exception were the correlation results of Cufflinks, which were substantially lower (ρ = 0.21-0.29 and 0.34-0.53). For both datasets we identified very low numbers of differentially expressed genes using the microarray platform. For RNA-Seq we checked the agreement of differentially expressed genes identified in the different pipelines and of GO-term enrichment results. CONCLUSION: In conclusion the combination of STAR aligner with HTSeq-Count followed by STAR aligner with RSEM and Sailfish generated differentially expressed genes best suited for the dataset at hand and in agreement with most of the other transcriptomics pipelines.
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    Influence of beta-blocker therapy on the risk of infections and death in patients at high risk for stroke induced immunodepression 

    Maier, Ilko L.; Becker, Johannes C.; Leyhe, Johanna Rosemarie; Schnieder, Marlena; Behme, Daniel; Psychogios, Marios-Nikos; Liman, Jan
    PLOS ONE 2018; 13(4): Art. e0196174
    BACKGROUND: Stroke-induced immunodepression is a well characterized complication of acute ischemic stroke. In experimental studies beta-blocker therapy reversed stroke-induced immunodepression, reduced infection rates and mortality. Recent, heterogeneous studies in stroke patients could not provide evidence of a protective effect of beta-blocker therapy. Aim of this study is to investigate the potential preventive effect of beta-blockers in subgroups of patients at high risk for stroke-induced immunodepression. METHODS: Data from a prospectively derived registry of major stroke patients receiving endovascular therapy between 2011-2017 in a tertiary stroke center (University Medical Center Göttingen. Germany) was used. The effect of beta-blocker therapy on pneumonia, urinary tract infection, sepsis and mortality was assessed using multivariate logistic regression analysis. RESULTS: Three hundred six patients with a mean age of 72 ± 13 years and a median NIHSS of 16 (IQR 10.75-20) were included. 158 patients (51.6%) had pre-stroke- and continued beta-blocker therapy. Beta-blocker therapy did not reduce the incidence of pneumonia (OR 0.78, 95% CI 0.31-1.92, p = 0.584), urinary tract infections (OR 1.51, 0.88-2.60, p = 0.135), sepsis (OR 0.57, 0.18-1.80, p = 0.334) or mortality (OR 0.59, 0.16-2.17, p = 0.429). Strokes involving the insula and anterio-medial cortex increased the risk for pneumonia (OR 4.55, 2.41-8.56, p<0.001) and sepsis (OR 4.13, 1.81-9.43, p = 0.001), while right hemispheric strokes increased the risk for pneumonia (OR 1.60, 0.92-2.77, p = 0.096). There was a non-significantly increased risk for urinary tract infections in patients with beta-blocker therapy and insula/anterio-medial cortex strokes (OR 3.12, 95% CI 0.88-11.05, p = 0.077) with no effect of beta-blocker therapy on pneumonia, sepsis or mortality in both subgroups. CONCLUSIONS: In major ischemic stroke patients, beta-blocker therapy did not lower post-stroke infection rates and was associated with urinary tract infections in a subgroup with insula/anterio-medial strokes.
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    MicroRNA Alterations in the Brain and Body Fluids of Humans and Animal Prion Disease Models: Current Status and Perspectives 

    Kanata, Eirini; Thüne, Katrin; Xanthopoulos, Konstantinos; Ferrer, Isidre; Dafou, Dimitra; Zerr, Inga; Sklaviadis, Theodoros; Llorens, Franc
    Frontiers in Aging Neuroscience 2018; 10: Art. 220
    Prion diseases are transmissible progressive neurodegenerative conditions characterized by rapid neuronal loss accompanied by a heterogeneous neuropathology, including spongiform degeneration, gliosis and protein aggregation. The pathogenic mechanisms and the origins of prion diseases remain unclear on the molecular level. Even though neurodegenerative diseases, including prion diseases, represent distinct entities, their pathogenesis shares a number of features including disturbed protein homeostasis, an overload of protein clearance pathways, the aggregation of pathological altered proteins, and the dysfunction and/or loss of specific neuronal populations. Recently, direct links have been established between neurodegenerative diseases and miRNA dysregulated patterns. miRNAs are a class of small non-coding RNAs involved in the fundamental post-transcriptional regulation of gene expression. Studies of miRNA alterations in the brain and body fluids in human prion diseases provide important insights into potential miRNA-associated disease mechanisms and biomarker candidates. miRNA alterations in prion disease models represent a unique tool to investigate the cause-consequence relationships of miRNA dysregulation in prion disease pathology, and to evaluate the use of miRNAs in diagnosis as biomarkers. Here, we provide an overview of studies on miRNA alterations in human prion diseases and relevant disease models, in relation to pertinent studies on other neurodegenerative diseases.
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    The Presynaptic Protein Mover Is Differentially Expressed Across Brain Areas and Synapse Types 

    Wallrafen, Rebecca; Dresbach, Thomas
    Frontiers in Neuroanatomy 2018; 12: Art. 58
    The assembly and function of presynaptic nerve terminals relies on evolutionarily conserved proteins. A small number of presynaptic proteins occurs only in vertebrates. These proteins may add specialized functions to certain synapses, thus increasing synaptic heterogeneity. Here, we show that the vertebrate-specific synaptic vesicle (SV) protein mover is differentially distributed in the forebrain and cerebellum of the adult mouse. Using a quantitative immunofluorescence approach, we compare the expression of mover to the expression of the general SV marker synaptophysin in 16 brain areas. We find that mover is particularly abundant in the septal nuclei (SNu), ventral pallidum (VPa), amygdala and hippocampus. Within the hippocampus, mover is predominantly associated with excitatory synapses. Its levels are low in layers that receive afferent input from the entorhinal cortex, and high in layers harboring intrahippocampal circuits. In contrast, mover levels are high in all nuclei of the amygdala, and mover is associated with inhibitory synapses in the medioposterior amygdala. Our data reveal a striking heterogeneity in the abundance of mover on three levels, i.e., between brain areas, within individual brain areas and between synapse types. This distribution suggests a role for mover in providing specialization to subsets of synapses, thereby contributing to the functional diversity of brain areas.
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    Hemodiafiltration Treatment for Severe Valproic Acid Intoxication: Case Report and Updated Systematic Literature Review 

    Tichelbäcker, Tobias; Herath, Judith; Tampe, Björn; Korsten, Peter
    Frontiers in Medicine 2018; 5
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    Endothelial progenitor cells (EPC) in sepsis with acute renal dysfunction (ARD). 

    Patschan, Susann A; Patschan, Daniel; Temme, Johanna; Korsten, Peter; Wessels, Johannes T; Koziolek, Michael; Henze, Elvira; Müller, Gerhard A
    Critical care (London, England) 2011; 15(2) p.R94-R94
    INTRODUCTION: Sepsis is characterized by systemic microvascular dysfunction. Endothelial progenitor cells (EPCs) are critically involved in maintaining vascular homeostasis under both physiological and pathological conditions. The aim of the present study was to analyze the endothelial progenitor cell system in patients suffering from sepsis with acute renal dysfunction. METHODS: Patients with newly diagnosed sepsis were recruited from the ICU in a nonrandomized prospective manner. Blood samples were obtained within the first 12 hours after the diagnosis of sepsis. For quantifying endothelial progenitor cells (EPCs), CD133+/Flk-1+ cells were enumerated by cytometric analysis. Analysis of EPC proliferation was performed by a colony-forming units (CFU) assay. Blood concentrations of proangiogenic mediators were measured by ELISA. Acute renal dysfunction was diagnosed according to the Acute Kidney Injury Network (AKIN) criteria. Depending on the overall mean creatinine concentration during the stay at the ICU, patients were either assigned to a 'normal creatinine group' or to a 'high creatinine group'. Survival rates, frequency of dialysis, the simplified acute physiology score (SAPS) II scores, and different laboratory parameters were collected/used for further clinical characterization RESULTS: Circulating EPCs were significantly higher in all sepsis patients included in the study as opposed to healthy controls. Patients within the 'high creatinine group' showed an even more pronounced EPC increase. In contrast, EPC proliferation was severely affected in sepsis. Neither total circulating EPCs nor EPC proliferation differed between patients requiring dialysis and patients without renal replacement therapy. Cell numbers and cell proliferation also did not differ between surviving patients and patients with sepsis-related death. Serum levels of vascular endothelial growth factor (VEGF), stromal derived factor-1 (SDF-1), and Angiopoietin-2 were higher in sepsis than in healthy controls. Sepsis patients within the 'high creatinine group' showed significantly higher mean serum levels of uric acid. CONCLUSIONS: Sepsis significantly affects the endothelial progenitor cell system, as reflected by increased EPC numbers, increased concentrations of proangiogenic mediators, and reduced proliferative capacity of the cells. This occurs independently from the frequency of dialysis and from patient survival. Increased serum levels of uric acid are possibly responsible for stronger EPC mobilization in sepsis patients with higher average creatinine levels.
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    Idiopathic combined, autoantibody-mediated ADAMTS-13/factor H deficiency in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in a 17-year-old woman: a case report. 

    Patschan, Daniel; Korsten, Peter; Behlau, Arne; Vasko, Radovan; Heeg, Malte; Sweiss, Nadera; Müller, Gerhard A; Koziolek, Michael
    Journal of medical case reports 2011-12-29; 5 p.598-598
    INTRODUCTION: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome is a life-threatening condition with various etiopathogeneses. Without therapy approximately 90% of all patients die from the disease. CASE PRESENTATION: We report the case of a 17-year-old Caucasian woman with widespread hematomas and headache. Due to hemolytic anemia, thrombocytopenia, and schistocytosis, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was suspected and plasma exchange therapy was initiated immediately. Since her thrombocyte level did not increase during the first week of therapy, plasma treatment had to be intensified to a twice-daily schedule. Further diagnostics showed markedly reduced activities of both ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 - also known as von Willebrand factor-cleaving protease) and factor H. Test results for antibodies against both proteins were positive. While plasma exchange therapy was continued, rituximab was given once weekly for four consecutive weeks. After the last dose, thrombocytes and activities of ADAMTS-13 and factor H increased into the normal range. Our patient improved and was discharged from the hospital. CONCLUSIONS: Since no clinical symptoms/laboratory findings indicated a malignant or specific autoimmune-mediated disorder, the diagnosis made was thrombotic thrombocytopenic purpura-hemolytic uremic syndrome due to idiopathic combined, autoantibody-mediated ADAMTS-13/factor H deficiency.
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