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• Springer  (2,427)
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• 2018  (2,427)
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• 1
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Berlin : Springer
Keywords: Toxicology ; Pharmacology
Notes: This is a series title, single volumes see link below.
ISSN: 1940-6053
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• 2
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Berlin : Springer
Notes: This is a series title, single volumes see link below.
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• 3
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Berlin : Springer
Keywords: Diagnosis, Computer-Assisted ; Diagnostic Imaging ; Image Processing, Computer-Assisted ; Robotics ; Surgery, Computer-Assisted ; Therapy, Computer-Assisted
Notes: Latest issue consulted: 7th (Sept. 26-29, 2004).
Pages: v. : ill.
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• 4
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Berlin : Springer
Keywords: Biotechnology / methods
Notes: This is a series title, single volumes see link below.
ISSN: 1940-607X
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• 5
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Springer
Publication Date: 2018-03-12
Description: The current WHO/ISUP classification and grading system subdivides urothelial tumours into prognostically distinct categories. Understanding the molecular pathways involved in bladder cancer development can improve patient stratification and management. This study aims to investigate the relationship between Snail, Slug and E-cadherin expressions and clinico-pathological features of non-muscle invasive bladder carcinoma (NMIBC). All patients attending the same urological centre from January to May 2002, who were pathologically diagnosed with NMIBC, were enrolled in this longitudinal cohort study. E-cadherin, Snail and Slug protein expressions were assessed by immunohistochemical analysis and compared with follow-up data. The main outcome measures were recurrence and progression rates. The cohort under investigation included 43 patients (38 men and 5 women, mean age 67.7 ± 10.6 years). High-grade (HG) carcinomas were 20/43, with 10 invasive cases (pT1). Low-grade (LG) carcinomas were 23/43, with no invasive cases (pTa). Among the eight HGpTa cases with recurrence, strong Snail expression was detected in six (75%). Out of the 17 LGpTa patients who experienced recurrence, 12 (70.6%) showed strong positivity for Snail. Among the 10 HGpT1 cases, recurrence was observed in 4, of which, 3 (75%) stained intensely for Snail. The Kaplan-Meier curves showed significantly different recurrence rates for patients with strong or weak Snail reactivity ( p  = 0.027). E-cadherin and Slug expression did not correlate with any of the parameters considered. On multivariate analysis, Snail expression was recognised as an independent prognostic factor for tumour recurrence ( p  = 0.003). In our study population, Snail immunohistochemical overexpression proved to be related to tumour recurrence in patients affected by NMIBC.
Electronic ISSN: 1432-2307
Topics: Medicine
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• 6
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Springer
Publication Date: 2018-03-14
Description: Leptomeningeal spread and hydrocephalus are increasingly recognized as late disease complications of glioblastoma with almost a quarter of patients requiring early cerebrospinal fluid shunting. The neurosurgeon is challenged with maintaining shunt patency when tumor disease progression is rapid and adjuvant oncologic therapy has yet to be initiated. We describe our experience in treating a young female with diffuse glioblastoma leptomeningeal spread and communicating hydrocephalus who had several episodes of shunt obstruction due to intraluminal tumor cell-fibrin deposits. Regular intraventricular instillations of urokinase fibrinolytic therapy not only re-established shunt patency but also contributed to the resolution of her hydrocephalus.
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
Topics: Medicine
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• 7
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Springer
Publication Date: 2018-03-14
Description: The yeast Saccharomyces cerevisiae is widely used as a cell factory to produce recombinant proteins. However, S. cerevisiae naturally secretes only a few proteins, such as invertase and the mating alpha factor, a...
Electronic ISSN: 2191-0855
Topics: Biology
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• 8
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Springer
Publication Date: 2018-03-14
Description: Parkinson’s disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated α-synuclein in the peripheral nervous system. Pre-existing diabetes mellitus might be a risk factor for developing Parkinson’s disease, and indeed, nearly 60% of Parkinson’s disease patients are insulin resistant. Thus, we have investigated whether phosphorylated α-synuclein is deposited in pancreatic tissue of subjects with synucleinopathies. We studied pancreatic tissue from 39 subjects diagnosed with Parkinson’s disease, Lewy body Dementia or incidental Lewy bodies disease, as well as that from 34 subjects with diabetes mellitus and a normal neuropathological examination, and 52 subjects with a normal neuropathological examination. We examined the pancreatic accumulation of phosphorylated α-synuclein and of the islet amyloid polypeptide precursor (IAPP), an amyloidogenic protein that plays an unknown role in diabetes mellitus, but that can promote α-synuclein amyloid deposition in vitro. Moreover, we performed proximity ligation assays to assess whether these two proteins interact in the pancreas of these subjects. Cytoplasmic phosphorylated α-synuclein deposits were found in the pancreatic β cells of 14 subjects with Parkinson’s disease (93%), in 11 subjects with Lewy body Dementia (85%) and in 8 subjects with incidental Lewy body disease (73%). Furthermore, we found similar phosphorylated α-synuclein inclusions in 23 subjects with a normal neuropathological examination but with diabetes mellitus (68%) and in 9 control subjects (17%). In addition, IAPP/α-synuclein interactions appear to occur in patients with pancreatic inclusions of phosphorylated α-synuclein. The presence of phosphorylated α-synuclein inclusions in pancreatic β cells provides a new evidence of a mechanism that is potentially common to the pathogenesis of diabetes mellitus, PD and DLB. Moreover, the interaction of IAPP and α-synuclein in the pancreatic β cells of patients may represent a novel target for the development of strategies to treat these diseases.
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
Topics: Medicine
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• 9
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Springer
Publication Date: 2018-03-14
Description: The objective of this study was to construct a plasmid vector for EGFR-hm-1 and C-Junh-825 small interfering RNA (siRNA). EGFR-hm-1 and C-Jun-hm-825 oligonucleotide fragments were synthesized and short hairpin RNA (shRNA) were amplified by PCR. Plasmids were isolated from E. coli TOP10 bacterium by restriction enzyme digestion using pst1 and BamH1 and oligonucleotide fragments were cloned into the pSilencer plasmid containing the U6 promoter. Recombinant clones were generated by transforming JM109 competent cells with plasmid vectors containing shRNA molecules. 58 base-paired EGFR-hm-1 and 59 base-paired C-Jun-hm-825 oligonucleotide fragments were isolated. The fragments were 100% homologous with human sequences available on GenBank. The recombinant pSilencer1.0 vector containing a 58-bp EGFR-hm-1 and 59-bp C-Jun-hm-825 fragment was constructed. These vectors have the potential to be used as treatment to combat skin photoaging under UV exposure.
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
Topics: Medicine
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• 10
Publication Date: 2018-03-14
Description: We recently found that treatment of normal human melanocytes (NHMs) with the antioxidant astaxanthin (AX) suppresses the stem cell factor (SCF)-stimulated protein expression levels of microphthalmia-associated transcription factor (MITF) at 1.5 h and of tyrosinase and endothelin B receptor at 96 h post-treatment. Analysis of the signaling cascade(s) involved revealed that although the major SCF-activated signaling cascade that leads to CREB activation (the c-KIT/Shc/Raf-1/ERK/RSK/CREB axis) is not interrupted, the increased phosphorylation of CREB is significantly abrogated by AX. We show for the first time that treatment of NHMs with SCF activates the p38/mitogen and stress-activated kinase (MSK1) axis in a c-KIT dependent fashion. Interestingly, whereas AX does not abrogate the SCF-induced activation of p38, it does affect the increased phosphorylation of its downstream target, MSK1. The lineage connection of p38/MSK1 activation with CREB activation and its associated MITF expression is supported by our finding that while silencing MSK1 abolishes the activation of CREB and the subsequent increase in total MITF proteins at 15 min and at 1.5 h, respectively, post-stimulation with SCF, inhibitors of p38 and of MSK1 abrogate the SCF-induced increase in total MITF proteins at 1.5 h post-stimulation. These findings suggest that SCF-stimulated melanogenesis can be abrogated by interrupting MSK1 phosphorylation, providing evidence for involvement of the p38/MSK1/CREB/MITF axis, providing new evidence for the ROS depletion independent interruption by antioxidants of SCF-triggered signaling.
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
Topics: Medicine
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• 11
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Springer
Publication Date: 2018-03-14
Description: Carotenoids are the precursors of Vitamin A. They are cleaved by carotenoid oxygenase and then isomerized by retinoid isomerase. In this study, we identified a gene, Bombyx mori Carotenoid Oxygenases and Retinal Isomerase ( BmCORI ), which was the homolog of β-carotene 15,15′-monooxygenase and the retinal pigment epithelium protein of 65 kD. Further analysis indicated that the expression of BmCORI in silkworms was significantly higher in females than in males. We also found that the β-carotene content in BmCORI -expressed human embryonic kidney 293 cells was significantly lower than in the controls, while the lutein content showed a slight difference. These results suggested that BmCORI is related to carotenoid depletion, especially β-carotene depletion. Our research provides new insight into the study of BmCORI function.
Print ISSN: 0006-2928
Electronic ISSN: 1573-4927
Topics: Biology , Chemistry and Pharmacology
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• 12
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Springer
Publication Date: 2018-03-14
Description: Over the last two decades, we have witnessed a revolution in the field of Parkinson’s disease (PD) genetics. Great advances have been made in identifying many loci that confer a risk for PD, which has subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis. Despite this success, it is predicted that only a relatively small proportion of the phenotypic variability has been explained by genetics. Therefore, it is clear that common heritable components of disease are still to be identified. Dissecting the genetic architecture of PD constitutes a critical effort in identifying therapeutic targets and although such substantial progress has helped us to better understand disease mechanism, the route to PD disease-modifying drugs is a lengthy one. In this review, we give an overview of the known genetic risk factors in PD, focusing not on individual variants but the larger networks that have been implicated following comprehensive pathway analysis. We outline the challenges faced in the translation of risk loci to pathobiological relevance and illustrate the need for integrating big-data by noting success in recent work which adopts a broad-scale screening approach. Lastly, with PD genetics now progressing from identifying risk to predicting disease, we review how these models will likely have a significant impact in the future.
Print ISSN: 0302-766X
Electronic ISSN: 1432-0878
Topics: Biology , Medicine
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• 13
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Springer
Publication Date: 2018-03-14
Description: Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a large eukaryotic gene family that transports and regulates the metabolism of sterols and phospholipids. The original classification of the family based on oxysterol-binding activity belies the complex dual lipid-binding specificity of the conserved OSBP homology domain (OHD). Additional protein- and membrane-interacting modules mediate the targeting of select OSBP/ORPs to membrane contact sites between organelles, thus positioning the OHD between opposing membranes for lipid transfer and metabolic regulation. This unique subcellular location, coupled with diverse ligand preferences and tissue distribution, has identified OSBP/ORPs as key arbiters of membrane composition and function. Here, we will review how molecular models of OSBP/ORP-mediated intracellular lipid transport and regulation at membrane contact sites relate to their emerging roles in cellular and organismal functions.
Print ISSN: 1420-682X
Electronic ISSN: 1420-9071
Topics: Biology , Medicine
Published by Springer on behalf of Birkhäuser.
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• 14
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Springer
Publication Date: 2018-03-14
Description: We establish in this paper the equivalence between a Volterra integral equation of the second kind and a singular ordinary differential equation of the third order with two initial conditions and an integral b...
Print ISSN: 1687-2762
Electronic ISSN: 1687-2770
Topics: Mathematics
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• 15
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Springer
Publication Date: 2018-03-14
Description: Resistance to therapy is one of the prime causes for treatment failure in cancer and recurrent disease. In recent years, autophagy has emerged as an important cell survival mechanism in response to different stress conditions that are associated with cancer treatment and aging. Autophagy is an evolutionary conserved catabolic process through which damaged cellular contents are degraded after uptake into autophagosomes that subsequently fuse with lysosomes for cargo degradation, thereby alleviating stress. In addition, autophagy serves to maintain cellular homeostasis by enriching nutrient pools. Although autophagy can act as a double-edged sword at the interface of cell survival and cell death, increasing evidence suggest that in the context of cancer therapy-induced stress responses, it predominantly functions as a cell survival mechanism. Here, we provide an up-to-date overview on our current knowledge of the role of pro-survival autophagy in cancer therapy at the preclinical and clinical stages and delineate the molecular mechanisms of autophagy regulation in response to therapy-related stress conditions. A better understanding of the interplay of cancer therapy and autophagy may allow to unveil new targets and avenues for an improved treatment of therapy-resistant tumors in the foreseeable future.
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
Topics: Medicine
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• 16
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Springer
Publication Date: 2018-03-14
Description: By exerting pro- and anti-tumorigenic actions, tumor-infiltrating immune cells can profoundly influence tumor progression, as well as the success of anti-cancer therapies. Therefore, the quantification of tumor-infiltrating immune cells holds the promise to unveil the multi-faceted role of the immune system in human cancers and its involvement in tumor escape mechanisms and response to therapy. Tumor-infiltrating immune cells can be quantified from RNA sequencing data of human tumors using bioinformatics approaches. In this review, we describe state-of-the-art computational methods for the quantification of immune cells from transcriptomics data and discuss the open challenges that must be addressed to accurately quantify immune infiltrates from RNA sequencing data of human bulk tumors.
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
Topics: Medicine
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• 17
Publication Date: 2018-03-14
Description: Purpose Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed cancers worldwide with significantly high prevalence in Southern China. Chemoprevention of cancer with alkylating agent compounds could potentially reverse, suppress, or prevent cancer progression. Cisplatin (CIS) is an antineoplastic or cytotoxic platinum-based drug used for chemotherapy of different types of human cancers such as NPC. Nevertheless, the effects of CIS on the migration and invasion of human NPC cells and the underlying molecular mechanisms have not yet been fully scrutinized. Methods In this work, we tested the effect of CIS on the proliferation, migration and invasion of NPC cells. The results exhibited that this drug exerts remarkable inhibitory effects on the proliferation, migration and invasion of NPC cells in a dose-dependent manner. Western blotting and real time RT-PCR were used for expression analyses. Results We found that CIS treatment led to a dose-dependent inhibition of Endothelin-1 (ET1) expression, at protein as well as mRNA levels in NPC cells. CIS was also found to activate the expression of BTG1 in NPC cells. Moreover, mechanistic analyses revealed that CIS increased the expression of B cell translocation gene 1 (BTG1) to suppress the expression of ET1. Furthermore, we show that ET1 could not be induced in CIS-resistant cells with suppressed BTG1 expression, and subsequently demote the proliferation, migration and invasion of NPC cells. Conclusions These findings provided compelling evidence of the role of CIS in suppressing NPC metastasis and its underlying molecular mechanisms.
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
Topics: Medicine
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• 18
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Springer
Publication Date: 2018-03-14
Description: Circular RNAs (CircRNAs) are a type of non-coding RNAs (NcRNAs) with a closed annular structure. Until next-generation sequencing (NGS) is developed, the misunderstanding of circRNAs ‘splicing error’ has changed, and the mysterious veil of circRNAs has been revealed. NGS provides an approach to investigate circRNAs. Many scholars point out that circRNAs may play an important role in many diseases, especially cancer. At the same time, exosomes, as a kind of extracellular vesicles loaded with many contents, are a hotspot in recent years. They can act as ‘messengers’ between cells, especially in cancer. Lately, it is interesting circRNAs are enriched and stable in exosomes, also called exo-circRNAs, and there have been several articles on circRNAs associated with exosomes. In this review, we summarize the characteristics of circRNAs, especially its main functions. Then, we briefly introduce exosomes and their function in cancer. Finally, the known relation between circRNAs and exosomes is discussed. With further researches, exo-circRNAs may be a novel pathway for cancer diagnosis and targeted therapy.
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
Topics: Medicine
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• 19
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Springer
Publication Date: 2018-03-14
Description: Chromatin is a very long DNA–protein complex that controls the expression and inheritance of the genetic information. Chromatin is stored within the nucleus in interphase and further compacted into chromosomes during mitosis. This process, known as chromosome condensation, is essential for faithful segregation of genomic DNA into daughter cells. Condensin and cohesin, members of the structural maintenance of chromosomes (SMC) family, are fundamental for chromosome architecture, both for establishment of chromatin structure in the interphase nucleus and for the formation of condensed chromosomes in mitosis. These ring-shaped SMC complexes are thought to regulate the interactions between DNA strands by topologically entrapping DNA. How this activity shapes chromosomes is not yet understood. Recent high throughput chromosome conformation capture studies revealed how chromatin is reorganized during the cell cycle and have started to explore the role of SMC complexes in mitotic chromatin architecture. Here, we summarize these findings and discuss the conserved nature of chromosome condensation in eukaryotes. We highlight the unexpected finding that condensin-dependent intra-chromosomal interactions in mitosis increase within a distinctive distance range that is characteristic for an organism, while longer and shorter-range interactions are suppressed. This reveals important molecular insight into chromosome architecture.
Print ISSN: 0172-8083
Electronic ISSN: 1432-0983
Topics: Biology
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• 20
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Springer
Publication Date: 2018-03-14
Description: This review attempts to analyze the mechanism of action and immunity of class IIa bacteriocins. These peptides are promising alternative food preservatives and they have a great potential application in medical sciences. Class IIa bacteriocins act on the cytoplasmic membrane of Gram-positive cells dissipating the transmembrane electrical potential by forming pores. However, their toxicity and immunity mechanism remains elusive. Here we discuss the role of the mannose phosphotransferase system (man-PTS) as the receptor for class IIa bacteriocins and the influence of the membrane composition on the activity of these antimicrobial peptides. A model that is consistent with experimental results obtained by different researchers involves the non-specific binding of the bacteriocin to the negatively charged membrane of target bacteria. This step would facilitate a specific binding to the receptor protein, altering its functionality and forming an independent pore in which the bacteriocin is inserted in the membrane. An immunity protein could specifically recognize and block the pore. Bacteriocins function in bacterial ecosystems and energetic costs associated with their production are also discussed. Theoretical models based on solid experimental evidence are vital to understand bacteriocins mechanism of action and to promote new technological developments.
Print ISSN: 0172-8083
Electronic ISSN: 1432-0983
Topics: Biology
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• 21
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Springer
Publication Date: 2018-03-14
Description: The precise and controlled regulation of gene expression at transcriptional and post-transcriptional levels is crucial for the eukaryotic cell survival and functions. In eukaryotes, more than 100 types of post-transcriptional RNA modifications have been identified. The N 6 -methyladenosine (m 6 A) modification in mRNA is among the most common post-transcriptional RNA modifications known in eukaryotic organisms, and the m 6 A RNA modification can regulate gene expression. The role of yeast m 6 A methyltransferase (Ime4) in meiosis, sporulation, triacylglycerol metabolism, vacuolar morphology, and mitochondrial functions has been reported. Stress triggers triacylglycerol accumulation as lipid droplets. Lipid droplets are physically connected to the different organelles such as endoplasmic reticulum, mitochondria, and peroxisomes. However, the physiological relevance of these physical interactions remains poorly understood. In yeast, peroxisome is the sole site of fatty acid β-oxidation. The metabolic status of the cell readily governs the number and physiological function of peroxisomes. Under low-glucose or stationary-phase conditions, peroxisome biogenesis and proliferation increase in the cells. Therefore, we hypothesized a possible role of Ime4 in the peroxisomal functions. There is no report on the role of Ime4 in peroxisomal biology. Here, we report that IME4 gene deletion causes peroxisomal dysfunction under stationary-phase conditions in Saccharomyces cerevisiae ; besides, the ime4Δ cells showed a significant decrease in the expression of the key genes involved in peroxisomal β-oxidation compared to the wild-type cells. Therefore, identification and determination of the target genes of Ime4 that are directly involved in the peroxisomal biogenesis, morphology, and functions will pave the way to better understand the role of m 6 A methylation in peroxisomal biology.
Print ISSN: 0172-8083
Electronic ISSN: 1432-0983
Topics: Biology
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• 22
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Springer
Publication Date: 2018-03-14
Description: Recent experimental and computational work revealed that transcriptional terminators in Saccharomyces cerevisiae can terminate transcription coming from both directions. This mechanism helps budding yeast cope with the pervasive nature of transcription by limiting aberrant transcription from invading neighboring genes.
Print ISSN: 0172-8083
Electronic ISSN: 1432-0983
Topics: Biology
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• 23
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Springer
Publication Date: 2018-03-14
Description: Ribosome biogenesis is a crucial process for growth and constitutes the major consumer of cellular resources. This pathway is subjected to very stringent regulation to ensure correct ribosome manufacture with a wide variety of environmental and metabolic changes, and intracellular insults. Here we summarise our current knowledge on the regulation of ribosome biogenesis in Saccharomyces cerevisiae by particularly focusing on the feedback mechanisms that maintain ribosome homeostasis. Ribosome biogenesis in yeast is controlled mainly at the level of the production of both pre-rRNAs and ribosomal proteins through the transcriptional and post-transcriptional control of the TORC1 and protein kinase A signalling pathways. Pre-rRNA processing can occur before or after the 35S pre-rRNA transcript is completed; the switch between these two alternatives is regulated by growth conditions. The expression of both ribosomal proteins and the large family of transacting factors involved in ribosome biogenesis is co-regulated. Recently, it has been shown that the synthesis of rRNA and ribosomal proteins, but not of trans-factors, is coupled. Thus the so-called CURI complex sequesters specific transcription factor Ifh1 to repress ribosomal protein genes when rRNA transcription is impaired. We recently found that an analogue system should operate to control the expression of transacting factor genes in response to actual ribosome assembly performance. Regulation of ribosome biogenesis manages situations of imbalanced ribosome production or misassembled ribosomal precursors and subunits, which have been closely linked to distinct human diseases.
Print ISSN: 0172-8083
Electronic ISSN: 1432-0983
Topics: Biology
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• 24
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Springer
Publication Date: 2018-03-14
Description: The search for novel pathological and functional amyloids represents one of the most important tasks of contemporary biomedicine. Formation of pathological amyloid fibrils in the aging brain causes incurable neurodegenerative disorders such as Alzheimer’s, Parkinson’s Huntington’s diseases. At the same time, a set of amyloids regulates vital processes in archaea, prokaryotes and eukaryotes. Our knowledge of the prevalence and biological significance of amyloids is limited due to the lack of universal methods for their identification. Here, using our original method of proteomic screening PSIA–LC–MALDI, we identified a number of proteins that form amyloid-like detergent-resistant aggregates in Saccharomyces cerevisiae . We revealed in yeast strains of different origin known yeast prions, prion-associated proteins, and a set of proteins whose amyloid properties were not shown before. A substantial number of the identified proteins are cell wall components, suggesting that amyloids may play important roles in the formation of this extracellular protective sheath. Two proteins identified in our screen, Gas1 and Ygp1, involved in biogenesis of the yeast cell wall, were selected for detailed analysis of amyloid properties. We show that Gas1 and Ygp1 demonstrate amyloid properties both in vivo in yeast cells and using the bacteria-based system C-DAG. Taken together, our data show that this proteomic approach is very useful for identification of novel amyloids.
Print ISSN: 0172-8083
Electronic ISSN: 1432-0983
Topics: Biology
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• 25
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Springer
Publication Date: 2018-03-14
Description: The continued research in the isolation of novel bacterial strains is inspired by the fact that native microorganisms possess certain desired phenotypes necessary for recombinant microorganisms in the biotech industry. Most studies have focused on the isolation and characterization of strains from marine ecosystems as they present a higher microbial diversity than other sources. In this study, a marine bacterium, W5C, was isolated from red seaweed collected from Yeosu, South Korea. The isolate can utilize several natural polysaccharides such as agar, alginate, carrageenan, and chitin. Genome sequence and comparative genomics analyses suggest that strain W5C belongs to a novel species of the Cellulophaga genus, from which the name Cellulophaga omnivescoria sp. nov. is proposed. Its genome harbors 3,083 coding sequences and 146 carbohydrate-active enzymes (CAZymes). Compared to other reported Cellulophaga species, the genome of W5C contained a higher proportion of CAZymes (4.7%). Polysaccharide utilization loci (PUL) for agar, alginate, and carrageenan were identified in the genome, along with other several putative PULs. These PULs are excellent sources for discovering novel hydrolytic enzymes and pathways with unique characteristics required for biorefinery applications, particularly in the utilization of marine renewable biomass. The type strain is JCM 32108 T (= KCTC 13157BP T ).
Print ISSN: 0343-8651
Electronic ISSN: 1432-0991
Topics: Biology , Medicine
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• 26
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Springer
Publication Date: 2018-03-14
Description: Hintergrund und Fragestellung Die Umsetzung der Leitlinienempfehlungen bezüglich der Diagnose und Therapie des Lipödems und Lymphödems scheint im Alltag Probleme zu bereiten. Daten dazu für die Versorgung in Deutschland sind rar. Ziel war eine Datensammlung zur Diagnostik und Therapie lymphologischer Erkrankungen im ambulanten Setting. Methoden Es erfolgte eine monozentrisch, prospektive Befragung von Patienten der lymphologischen ambulanten Sprechstunde mithilfe eines standardisierten Fragebogens zu Diagnostik und Therapie des Lipödems und Lymphödems bei Erstdiagnose. Ergebnisse Eingeschlossen wurden 72 Patienten (83,3 % Frauen) mit einem im Venenzentrum der Dermatologischen und Gefäßchirurgischen Kliniken diagnostisch gesicherten Lymphödem ( n  = 26), Lipödem ( n  = 14) oder Lipolymphödem ( n  = 32); 44,4 % hatten mehr als 5 Jahre vor Erstdiagnose Beschwerden. Die häufigsten Beschwerden waren Bein- und Fußschwellungen (besonders Lymphödem) und Schweregefühl (besonders Lipödem). In 75 % der Fälle wurde die Erstdiagnose durch einen Facharzt gestellt. Die von den Leitlinien empfohlene lymphologische Basisdiagnostik aus Anamnese (73,6 %) und klinischer Untersuchung (84,7 %) fand mehrheitlich statt. Nach der Erstdiagnose erhielten 46 % der Patienten eine Entstauungsphase von unterschiedlicher Qualität und Intensität; 58,3 % der Patienten erhielten unmittelbar eine Kompressionsstrumpfversorgung. Anleitungen zu Atemübungen (22,2 %), Eigendrainage (6,9 %) oder Muskelübungen (8,3 %) fanden nur bei wenigen Patienten statt. Diskussion Es bestehen weiterhin Defizite in der Diagnostik und insbesondere der Therapie lymphologischer Erkrankungen im ambulanten Setting. Fortbildungs- und Schulungsangebote für Ärzte, Physiotherapeuten und Fachhandel sowie aber auch für Patienten sind sinnvoll und notwendig.
Print ISSN: 0017-8470
Electronic ISSN: 1432-1173
Topics: Medicine
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• 27
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Springer
Publication Date: 2018-03-14
Electronic ISSN: 1433-0563
Topics: Medicine
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• 28
Publication Date: 2018-03-14
Description: In the original publication [1] were several parts incorrect. The corrected versions can be found below. The original article has been updated to rectify these errors.
Print ISSN: 1687-1472
Electronic ISSN: 1687-1499
Topics: Electrical Engineering, Measurement and Control Technology , Computer Science
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• 29
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Springer
Publication Date: 2018-03-14
Description: The major challenges in biophysical characterization of human protein–carbohydrate interactions are obtaining monodispersed preparations of human proteins that are often post-translationally modified and lack of detection of carbohydrates by traditional detection systems. Light scattering (dynamic and static) techniques offer detection of biomolecules and their complexes based on their size and shape, and do not rely on chromophore groups (such as aromatic amino acid sidechains). In this study, we utilized dynamic light scattering, analytical ultracentrifugation and small-angle X-ray scattering techniques to investigate the solution properties of a complex resulting from the interaction between a 15 kDa heparin preparation and miniagrin, a miniaturized version of agrin. Results from dynamic light scattering, sedimentation equilibrium, and sedimentation velocity experiments signify the formation of a monodisperse complex with 1:1 stoichiometry, and low-resolution structures derived from the small-angle X-ray scattering measurements implicate an extended conformation for a side-by-side miniagrin‒heparin complex.
Print ISSN: 0175-7571
Electronic ISSN: 1432-1017
Topics: Biology , Physics
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• 30
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Springer
Publication Date: 2018-03-14
Description: The correct Author names are shown in this paper.
Print ISSN: 0031-6970
Electronic ISSN: 1432-1041
Topics: Chemistry and Pharmacology , Medicine
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• 31
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Springer
Publication Date: 2018-03-14
Description: Purpose Everolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients’ home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients. Methods Paired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of ± 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted. Results Samples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93–1.35) and a small proportional bias (slope 0.89; 95% CI 0.76–0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of 〈 20%. Conclusions DBS is a valid method to determine everolimus concentrations in cancer patients. This can especially be of value for early recognition of over- or underexposure to enable dose adaptations.
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Publication Date: 2018-03-14
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Springer
Publication Date: 2018-03-14
Description: Purpose Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. Methods In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2. In cohort 3, subjects received 10-mg venetoclax doses on day 1 of period 1 and days 1 and 11 of period 2, and 50 mg ritonavir daily on days 1 to 14 of period 2. Results Single doses of 50 and 100 mg ritonavir increased the venetoclax maximum concentration ( C max ) 2.3- to 2.4-fold compared to venetoclax alone and the area under the curve (AUC) 6.1- and 8.1-fold, respectively. Daily 50 mg ritonavir resulted in a 2.4- and 7.9-fold increase in venetoclax C max and AUC, respectively. Administration of 50 mg ritonavir daily saturated CYP3A inhibition and completely inhibited the formation of the major venetoclax metabolite M27. Time-dependent CYP3A inhibition with daily 50 mg ritonavir was offset by ritonavir CYP3A induction, resulting in a limited net increase in CYP3A inhibition with multiple doses. Conclusion After completion of the dose ramp-up, venetoclax dose reductions of at least 75% are recommended when administered concomitantly with strong CYP3A inhibitors to maintain venetoclax exposures within the established therapeutic window for CLL treatment.
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Publication Date: 2018-03-14
Description: Purpose Bleeding is one of the possible adverse events during clopidogrel therapy. The CYP2C19 gene is the most significant genetic factor which influences response to clopidogrel treatment. We aimed to examine the contribution of the CYP2C19 gene to bleeding occurrence during clopidogrel therapy in Serbian patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Methods This case–control study included 53 patients who experienced bleeding and 55 patients without bleeding. Bleeding events were defined and classified using the Bleeding Academic Research Consortium (BARC) criteria. All patients were prescribed daily doses of clopidogrel during the 1-year follow-up after PCI. The CYP2C19*17 (c.-806C〉T, rs12248560), rs11568732 (c.-889T〉G, CYP2C19*20 ), CYP2C19*2 (c.681G〉A; rs4244285) and CYP2C19*3 (c.636G〉A; rs4986893) variants were analysed in all 108 patients. Additionally, sequencing of all nine exons, 5′UTR and 3′UTR in the rs11568732 carriers was performed. Results Association between bleeding (BARC type ≥ 2) and the CYP2C19*17 variant was not observed [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.2–1.1; p  = 0.107). The rs11568732 variant showed significant association with bleeding (OR, 3.7; 95% CI, 1.12–12.44; p  = 0.025). Also, we found that the rs11568732 variant appears independently of haplotype CYP2C19*3B , which is contrary to the previous findings. Conclusions Our results indicate the absence of CYP2C19*17 influence and turn the attention to the potential significance of the rs11568732 variant in terms of adverse effects of clopidogrel. However, it is necessary to conduct an independent conformation study in order to verify this finding. Also, an analysis of the functional implication of the rs11568732 variant is necessary in order to confirm the significance of this variant, both in relation to its influence on gene expression and in relation to its medical significance.
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Publication Date: 2018-03-14
Description: Purpose Inhaled drug delivery is an attractive route by which to deliver drugs to lungs of patients with idiopathic pulmonary fibrosis (IPF). GSK3008348 is a potent and selective small molecule being developed as the first inhaled inhibitor of the αvβ6 integrin for the treatment of IPF. The phase 1 first-time-in-human clinical trial (NCT02612051) presented here was designed to investigate the safety, tolerability and pharmacokinetic (PK) profile of single doses of GSK3008348 in healthy participants. Methods Single ascending doses of GSK3008348 were administered to three cohorts of eight healthy participants in a randomised, double-blind, placebo-controlled, 4-period crossover design. Safety, tolerability and PK were assessed after single doses of 1–3000 mcg given by nebulisation. Results A total of 29 participants were enrolled and received at least one dose of study treatment. There were no serious adverse events (AE) reported in any participant. No trends or clinically important differences were noted in the incidence or intensity of AEs or other safety assessments. Maximum plasma concentrations of GSK3008348 were generally attained within approximately 30 min after start of nebulisation, with geometric mean terminal elimination half-lives ranging from 7.95 to 10.2 h. Exposures, as measured by area under the plasma concentration-time curve (AUC), were dose proportional across all doses where estimates were possible (100–3000 mcg). Dose normalised geometric mean C max increased with dose up to 3000 mcg. This supra proportionality was relatively modest, with a less than 3-fold increase over the range from 30 to 3000 mcg. The reason(s) for this observation are currently not known but may be due to slower absorption at the lowest doses. All exposures were within the exposure margins set by the non-clinical toxicity studies and so this is not expected to have any impact on safety. Conclusions In summary, GSK3008348 was well tolerated at single doses up to 3000 mcg in healthy participants, and its PK profile was dose proportional at potentially clinically relevant doses (300–3000 mcg). These findings support further development of GSK3008348 as a novel inhaled treatment option for IPF.
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Publication Date: 2018-03-14
Description: Background and aims Aging is associated with a deregulation of biological systems that lead to an increase in oxidative stress, inflammation, and apoptosis, among other effects. Xanthohumol is the main preylated chalcone present in hops ( Humulus lupulus L.) whose antioxidant, anti-inflammatory and chemopreventive properties have been shown in recent years. In the present study, the possible protective effects of xanthohumol on liver alterations associated with aging were evaluated. Methods Male young and old senescence-accelerated prone mice (SAMP8), aged 2 and 10 months, respectively, were divided into four groups: non-treated young, non-treated old, old treated with 1 mg/kg/day xanthohumol, and old treated with 5 mg/kg/day xanthohumol. Male senescence-accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed and livers were collected. mRNA (AIF, BAD, BAX, Bcl-2, eNOS, HO-1, IL-1β, NF-κB2, PCNA, sirtuin 1 and TNF-α) and protein expressions (BAD, BAX, AIF, caspase-3, Blc-2, eNOS, iNOS, TNF-α, IL1β, NF-κB2, and IL10) were measured by RT-PCR and Western blotting, respectively. Mean values were analyzed using ANOVA. Results A significant increase in mRNA and protein levels of oxidative stress, pro-inflammatory and proliferative markers, as well as pro-apoptotic parameters was shown in old non-treated SAMP8 mice compared to the young SAMP8 group and SAMR1 mice. In general, age-related oxidative stress, inflammation and apoptosis were significantly decreased ( p  〈 0.05) after XN treatment. In most cases, this effect was dose-dependent. Conclusions XN was shown to modulate inflammation, apoptosis, and oxidative stress in aged livers, exerting a protective effect in hepatic alterations.
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Electronic ISSN: 1436-6215
Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
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Publication Date: 2018-03-14
Description: One of the characteristic features of the human motor system is redundancy—i.e., the ability to achieve a given task outcome using multiple coordination patterns. However, once participants settle on using a specific coordination pattern, the process of learning to use a new alternative coordination pattern to perform the same task is still poorly understood. Here, using two experiments, we examined this process of how participants shift from one coordination pattern to another using different reinforcement schedules. Participants performed a virtual reaching task, where they moved a cursor to different targets positioned on the screen. Our goal was to make participants use a coordination pattern with greater trunk motion, and to this end, we provided reinforcement by making the cursor disappear if the trunk motion during the reach did not cross a specified threshold value. In Experiment 1, we compared two reinforcement schedules in two groups of participants—an abrupt group, where the threshold was introduced immediately at the beginning of practice; and a gradual group, where the threshold was introduced gradually with practice. Results showed that both abrupt and gradual groups were effective in shifting their coordination patterns to involve greater trunk motion, but the abrupt group showed greater retention when the reinforcement was removed. In Experiment 2, we examined the basis of this advantage in the abrupt group using two additional control groups. Results showed that the advantage of the abrupt group was because of a greater number of practice trials with the desired coordination pattern. Overall, these results show that reinforcement can be successfully used to shift coordination patterns, which has potential in the rehabilitation of movement disorders.
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Publication Date: 2018-03-14
Description: Purpose The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism. Methods In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism. Primary PK parameters were generated using the SimCYP and WinNonlin software. Results Correlation analysis suggested that CYP2C9 is the main enzyme responsible for siponimod metabolism in humans. Compared with the CYP2C9*1/*1 genotype, HLM incubations from CYP2C9*3/*3 and CYP2C9*2/*2 donors showed ~ 10- and 3-fold decrease in siponimod metabolism, respectively. Simulations of enzyme contribution predicted that in the CYP2C9*1/*1 genotype, CYP2C9 is predominantly responsible for siponimod metabolism (~ 81%), whereas in the CYP2C9*3/*3 genotype, its contribution is reduced to 11%. The predicted exposure increase of siponimod with fluconazole 200 mg was 2.0–2.4-fold for CYP2C9*1/*1 genotype. In context of single dosing, the predicted mean area under the curve (AUC) is 2.7-, 3.0- and 4.5-fold higher in the CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, compared with the CYP2C9*1/*1 genotype. Conclusion .Enzyme phenotyping with correlation analysis confirmed the predominant role of CYP2C9 in the biotransformation of siponimod and demonstrated the functional consequence of CYP2C9 genetic polymorphism on siponimod metabolism. Simulation of fluconazole inhibition closely predicted a 2-fold AUC change (ratio within ~ 20% deviation) to the observed value. In silico simulation predicted a significant reduction in siponimod clearance in the CYP2C9*2/*2 and CYP2C9*3/*3 genotypes based on the in vitro metabolism data; the predicted exposure was close (within 30%) to the observed results for the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes.
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Springer
Publication Date: 2018-03-14
Description: Purpose Limited studies have examined red meat consumption in relation to risk of chronic obstructive pulmonary disease (COPD), and none have examined the impact of long-term diet on COPD risk. We sought to investigate the association between long-term red meat consumption and risk of COPD. Methods The population-based prospective Swedish Mammography Cohort included 34,053 women, aged 48–83 years, followed for the current analyses from 2002 to 2014. Unprocessed and processed red meat consumption was assessed with a self-administered questionnaire in 1987 and 1997. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Over a mean follow-up of 11.6 years (2002–2014; 393,831 person-years), 1488 COPD cases were ascertained via linkage to the Swedish health registers. A positive association between long-term processed red meat (average from 1987 to 1997) and risk of COPD was observed. In contrast, no association was observed with unprocessed red meat with corresponding HRs of 1.36 (95% CI 1.03–1.79) for processed and 0.87 (95% CI 0.74–1.02) for unprocessed red meat among women who consumed ≥ 50 g/day compared to 〈 25 g/day. The observed association with processed meat was confined to ex-smokers ( P for interaction = 0.30); women consuming of ≥ 50 g/day of processed meat had a 2.3-fold (95% CI 1.24–4.12) higher risk of COPD than those consuming 〈 25 g/day. No similar associations were observed among current or never smokers. Conclusion In this prospective cohort of women with moderate red meat consumption, long-term processed red meat consumption was associated with an increased risk of COPD particularly among ex-smokers.
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Publication Date: 2018-03-14
Description: Measures of causal effects play a central role in epidemiology. A wide range of measures exist, which are designed to give relevant answers to substantive epidemiological research questions. However, due to mathematical convenience and software limitations most studies only report odds ratios for binary outcomes and hazard ratios for time-to-event outcomes. In this paper we show how logistic regression models and Cox proportional hazards regression models can be used to estimate a wide range of causal effect measures, with the R -package stdReg . For illustration we focus on the attributable fraction, the number needed to treat and the relative excess risk due to interaction. We use two publicly available data sets, so that the reader can easily replicate and elaborate on the analyses. The first dataset includes information on 487 births among 188 women, and the second dataset includes information on 2982 women diagnosed with primary breast cancer.
Print ISSN: 0393-2990
Electronic ISSN: 1573-7284
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Springer
Publication Date: 2018-03-14
Description: Studies of the effects of physical activity on cognition suggest that aerobic fitness can improve cognitive abilities. However, the physiological mechanisms for the cognitive benefit of aerobic fitness are less well understood. We examined the association between aerobic fitness and cerebrovascular function with neurocognitive functions in healthy, young adults. Participants aged 18–29 years underwent measurements of cerebral vasomotor reactivity (CVMR) in response to rebreathing-induced hypercapnia, maximal oxygen uptake ( V O 2 max) during cycle ergometry to voluntary exhaustion, and simple- and complex-neurocognitive assessments at rest. Ten subjects were identified as having low-aerobic fitness (LF 〈 15th fitness percentile), and twelve subjects were identified as having high-aerobic fitness (HF 〉 80th fitness percentile). There were no LF versus HF group differences in cerebrovascular hemodynamics during the baseline condition. Changes in middle cerebral artery blood velocity and CVMR during hypercapnia were elevated more in the HF than the LF group. Compared to the LF, the HF performed better on a complex-cognitive task assessing fluid reasoning, but not on simple attentional abilities. Statistical modeling showed that measures of V O 2 max, CVMR, and fluid reasoning were positively inter-correlated. The relationship between V O 2 max and fluid reasoning, however, did not appear to be reliably mediated by CVMR. In conclusion, a high capacity for maximal oxygen uptake among healthy, young adults was associated with greater CVMR and better fluid reasoning, implying that high-aerobic fitness may promote cerebrovascular and cognitive functioning abilities.
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Publication Date: 2018-03-14
Description: The swim bladder of fish is an internal gas-filled organ that allows fish to control their buoyancy and swimming depth. Fish maws (the dried swim bladders of fish) have been used over many centuries as traditional medicines, tonics and a luxurious gourmet food in China and Southeast Asia. Little is known about the structural information of polysaccharides comprising this important functional material of fish tissue. In the present study, the total glycosaminoglycan (GAG) from fish maw was characterized. Two GAGs were identified, chondroitin sulfate (CS, having a molecular weight of 18–40 kDa) and heparan sulfate (HS), corresponding to 95% and 5% of the total GAG, respectively. Chondroitinase digestion showed that the major CS GAG was composed of ΔUA-1 → 3-GalNAc4S (59.7%), ΔUA-1 → 3-GalNAc4,6S (36.5%), ΔUA-1 → 3-GalNAc6S (2.2%) and ΔUA-1 → 3-GalNAc (1.6%) disaccharide units. 1 H–NMR analysis and degradation with specific chondroitinases, both CS-type A/C and CS-type B were present in a ratio of 1.4:1. Analysis using surface plasmon resonance showed that fibroblast growth factor (FGF)-2 bound to the CS fraction (K D  = 136 nM). These results suggest that this CS may be involved in FGF-signal pathway, mediating tissue repair, regeneration and wound healing. The CS, as the major GAG in fish maw, may have potential pharmacological activity in accelerating wound healing.
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Publication Date: 2018-03-14
Description: The intestinal pathogen Escherichia coli serotype O104:H4 (ECO104) can cause bloody diarrhea and haemolytic uremic syndrome. The ECO104 O antigen has the unique repeating unit structure [4Galα1–4Neu5,7,9Ac 3 α2–3Galβ1–3GalNAcβ1-], which includes the mammalian sialyl-T antigen as an internal structure. Previously, we identified WbwC from ECO104 as the β3Gal-transferase that synthesizes the T antigen, and showed that α3-sialyl-transferase WbwA transfers sialic acid to the T antigen. Here we identify the wbwB gene product as a unique α1,4-Gal-transferase WbwB that transfers Gal from UDP-Gal to the terminal sialic acid residue of Neu5Acα2–3Galβ1–3GalNAcα-diphosphate-lipid acceptor. NMR analysis of the WbwB enzyme reaction product indicated that Galα1-4Neu5Acα2–3Galβ1–3GalNAcα-diphosphate-lipid was synthesized. WbwB from ECO104 has a unique acceptor specificity for terminal sialic acid as well as the diphosphate group in the acceptor. The characterization studies showed that WbwB does not require divalent metal ion as a cofactor. Mutagenesis identified Lys243 within an RKR motif and both Glu315 and Glu323 of the fourth EX 7 E motif as essential for the activity. WbwB is the final glycosyltransferase in the biosynthesis pathway of the ECO104 antigen repeating unit. This work contributes to knowledge of the biosynthesis of bacterial virulence factors.
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Publication Date: 2018-03-14
Description: One of the author’s middle name of this article was incorrectly published as “Emmanouil E. Pappou.” This is now presented correctly in this article as “Emmanouil P. Pappou.”
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Publication Date: 2018-03-14
Description: Purpose This study set out to compare the in-hospital outcomes of early elective and elective laparoscopic sigmoidectomy due to diverticulitis. Methods We examined the data for 378 diverticulitis patients who received an elective laparoscopic sigmoid resection between 2008 and 2012. We divided the patients into two groups: elective (group A, n  = 278) and early elective (group B, n  = 100). Patients in group A received surgery during the inflammation-free interval, and those in group B immediately after treating the attack with IV antibiotics for a mean period of 8 days (IQR = 3). Results Overall mortality was 0%. The mean operation duration was the same in both groups being 77.5 and 80 min respectively. There was no significant difference in the outcomes between the two groups, measured using the Clavien-Dindo classification of surgical complication (CCSC; p  = 0.992). A revision due to complications was necessary in 16 cases (group A) and six cases (group B) ( p  = 0.820). The conversion rate to open surgery was low (six individuals in group A, vs. four in group B; p  = 0.331). Patients in group B suffered significantly fewer diverticulitis attacks (three in group A, vs. two in group B; p  = 0.026). Conclusion Our study showed no difference in outcome between elective and early elective cases. Operation durations were optimal in both cases and were 50% shorter than those recorded in the literature. An early elective operation represents a good treatment option, especially for patients suffering from complicated diverticulitis.
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Publication Date: 2018-03-14
Description: Purpose Damage control strategy (DCS) is a two-staged procedure for the treatment of perforated diverticular disease complicated by generalized peritonitis. The aim of this retrospective multicenter cohort study was to evaluate the prognostic impact of an ongoing peritonitis at the time of second surgery. Methods Consecutive patients who underwent DCS for perforated diverticular disease of the sigmoid colon with generalized peritonitis at four surgical centers were included. Damage control strategy is a two-stage emergency procedure: limited resection of the diseased colonic segment, closure of oral and aboral colon, and application of a negative pressure assisted abdominal closure system at the initial surgery followed by second laparotomy 48 h later. Therein, decision for definite reconstruction (anastomosis or Hartmann’s procedure (HP)) is made. An ongoing peritonitis at second surgery was defined as presence of visible fibrinous, purulent, or fecal peritoneal fluid. Microbiologic findings from peritoneal smear at first surgery were collected and analyzed. Results Between 5/2011 and 7/2017, 74 patients underwent a DCS for perforated diverticular disease complicated by generalized peritonitis (female: 40, male: 34). At second surgery, 55% presented with ongoing peritonitis (OP). Patients with OP had higher rate of organ failure (32 vs. 9%, p  = 0.024), higher Mannheim Peritonitis Index (25.2 vs. 18.9; p  = 0.001), and increased operation time (105 vs. 84 min., p  = 0.008) at first surgery. An anastomosis was constructed in all patients with no OP (nOP) at second surgery as opposed to 71% in the OP group ( p  〈 0.001). Complication rate (44 vs. 24%, p  = 0.092), mortality (12 vs. 0%, p  = 0.061), overall number of surgeries (3.4 vs. 2.4, p  = 0.017), enterostomy rate (76 vs. 36%, p  = 0.001), and length of hospital stay (25 vs. 18.8 days, p  = 0.03) were all increased in OP group. OP at second surgery occurred significantly more often in patients with Enterococcus infection (81 vs. 44%, p  = 0.005) and with fungal infection (100 vs. 49%, p  = 0.007). In a multivariate analysis, Enterococcus infection was associated with increased morbidity (67 vs. 21%, p  〈 0.001), enterostomy rate (81 vs. 48%, p  = 0.017), and anastomotic leakage (29 vs. 6%, p  = 0.042), whereas fungal peritonitis was associated with an increased mortality (43 vs. 4%, p  = 0.014). Conclusion Ongoing peritonitis after DCS is a predictor of a worse outcome in patients with perforated diverticulitis. Enterococcal and fungal infections have a negative impact on occurrence of OP and overall outcome.
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Publication Date: 2018-03-14
Description: A bstract Despite extensive searches for an additional neutral massive gauge boson at the LHC, a Z ′ at the weak scale could still be present if its couplings to the first two generations of quarks are suppressed, in which case the production in hadron colliders relies on tree-level processes in association with heavy flavors or one-loop processes in association with a jet. We consider the low-energy effective theory of a top-philic Z ′ and present possible UV completions. We clarify theoretical subtleties in evaluating the production of a top-philic Z ′ at the LHC and examine carefully the treatment of ananomalous Z ′ current in the low-energy effective theory. Recipes for properly computing the production rate in the Z ′ + j channel are given. We discuss constraints from colliders and low-energy probes of new physics. As an application, we apply these considerations to models that use a weak-scale Z ′ to explain possible violations of lepton universality in B meson decays, and show that the future running of a high luminosity LHC can potentially cover much of the remaining parameter space favored by this particular interpretation of the B physics anomaly.
Electronic ISSN: 1029-8479
Topics: Physics
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Publication Date: 2018-03-14
Description: A bstract We consider the Riemann-Hilbert factorization approach to solving the field equations of dimensionally reduced gravity theories. First we prove that functions belonging to a certain class possess a canonical factorization due to properties of the underlying spectral curve. Then we use this result, together with appropriate matricial decompositions, to study the canonical factorization of non-meromorphic monodromy matrices that describe deformations of seed monodromy matrices associated with known solutions. This results in new solutions, with unusual features, to the field equations.
Electronic ISSN: 1029-8479
Topics: Physics
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Publication Date: 2018-03-14
Description: A bstract Next-to-leading order predictions matched to parton showers are compared with recent ATLAS data on isolated photon production and CMS data on associated photon and jet production in pp and pPb collisions at different centre-of-mass energies of the LHC. We find good agreement and, as expected, considerably reduced scale uncertainties compared to previous theoretical calculations. Predictions are made for the ratio of inclusive photons over decay photons R γ , an important quantity to evaluate the significance of additional photon sources, e.g. thermal radiation from a Quark-Gluon-Plasma, and for distributions in the parton momentum fraction in lead ions x Pb obs , that could be determined by ALICE, ATLAS, CMS and LHCb in ongoing analyses of photon+jet production in pPb collisions at $$\sqrt{s_{N\ N}} = 5.02$$ TeV. These data should have an important impact on the determination of nuclear effects such as shadowing at low x .
Electronic ISSN: 1029-8479
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Publication Date: 2018-03-14
Description: A bstract The emergent nature of spacetime geometry and black holes can be directly probed in simple holographic duals of higher spin gravity and tensionless string theory. To this end, we study time dependent thermal correlation functions of gauge invariant observables in suitably chosen free large N gauge theories. At low temperature and on short time scales the correlation functions encode propagation through an approximate AdS spacetime while interesting departures emerge at high temperature and on longer time scales. This includes the existence of evanescent modes and the exponential decay of time dependent boundary correlations, both of which are well known indicators of bulk black holes in AdS/CFT. In addition, a new time scale emerges after which the correlation functions return to a bulk thermal AdS form up to an overall temperature dependent normalization. A corresponding length scale was seen in equal time correlation functions in the same models in our earlier work.
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Publication Date: 2018-03-14
Description: A bstract In this note we study T-duality transformations for the NS5-brane and its orbifolds along angular directions. We identify a geometric charge for these configurations and show that it is interchanged with the H -flux under T-duality. We furthermore perform a supersymmetry analysis and find that T-duality can break supersymmetry, in agreement with earlier results in the literature. We contrast our findings to compactifications of the NS5-brane on tori, which have vanishing geometric charge and for which T-duality transformations along the compact directions preserve supersymmetry. This shows that the uncompactified NS5-brane and the compactified-and-smeared solution have different properties and behave differently under T-duality.
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Springer
Publication Date: 2018-03-14
Description: A bstract We present new and explicit formulae for the one-loop integrands of scattering amplitudes in non-supersymmetric gauge theory and gravity, valid for any number of particles. The results exhibit the colour-kinematics duality in gauge theory and the double-copy relation to gravity, in a form that was recently observed in supersymmetric theories. The new formulae are expressed in a particular representation of the loop integrand, with only one quadratic propagator, which arises naturally from the framework of the loop-level scattering equations. The starting point in our work are the expressions based on the scattering equations that were recently derived from ambitwistor string theory. We turn these expressions into explicit formulae depending only on the loop momentum, the external momenta and the external polarisations. These formulae are valid in any number of spacetime dimensions for pure Yang-Mills theory (gluon) and its natural double copy, NS-NS gravity (graviton, dilaton, B-field), and we also present formulae in four spacetime dimensions for pure gravity (graviton). We perform several tests of our results, such as checking gauge invariance and directly matching our four-particle formulae to previously known expressions. While these tests would be elaborate in a Feynman-type representation of the loop integrand, they become straightforward in the representation we use.
Electronic ISSN: 1029-8479
Topics: Physics
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Springer
In: Lung
Publication Date: 2018-03-14
Description: Although included in the serological domain of the ‘interstitial pneumonia with auto-immune features’ (IPAF) research statement, the search for myositis-specific antibodies (MSA) is not incorporated in routine clinical practice. The objective of the study was to evaluate MSA prevalence in an idiopathic interstitial pneumonia (IIP) cohort ( n  = 68) with suggestive morphological interstitial lung disease patterns. Twelve of 68 patients (17.6%) carried MSA, whereof only two were anti-nuclear antibody-positive. Besides female gender, no demographic or pulmonary function parameter was predictive for MSA positivity. MSA were present in 32.4% of IPAF patients ( n  = 37), being essential for IPAF diagnosis in four of them (10.8%).
Print ISSN: 0341-2040
Electronic ISSN: 1432-1750
Topics: Medicine
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Springer
Publication Date: 2018-03-14
Description: Purpose Acute lung injury (ALI) is a fatal syndrome in critically ill patients. It is characterized by lung edema and inflammation. Numerous pro-inflammatory mediators are released into alveoli. Among them, interleukin-1beta (IL-1β) causes an increase in solute permeability across the alveolar-capillary barrier leading to edema. It activates key effector cells (alveolar epithelial and endothelial cells) releasing inflammatory chemokines and cytokines. The purpose of the study was to demonstrate that nebulized liposomes inhibit ALI in vivo . Methods In vivo ALI model was simulated through intra-tracheal instillation of IL-1β solution (100 μg/mL in PBS, pH 7.2, 200 μL) in male Sprague-Dawley rats. Various formulations were tested in ALI induced rats. These formulations include plain liposomes (PL), methylprednisolone sodium succinate solution (MPS solution), cRGD-peptide grafted liposomes (L cRGD ) and methylprednisolone sodium succinate encapsulated and cRGD-peptide grafted liposomes (MPS-L cRGD ). Formulations were nebulized in vivo in rats using micro-pump nebulizer. Results Liposome formulations exhibited higher levels of drug concentration in lungs. The physicochemical parameters demonstrated that the liposome formulations were stable. On the basis of aerodynamic droplet-size, nebulized formulations were estimated to deposit in different regions of respiratory tract, especially alveolar region, Among the formulations, MPS-L cRGD caused significant reduction of edema, neutrophil infiltration and inflammation biochemical marker levels. Conclusion From the results, it can be inferred that nebulization of targeted liposomes had facilitated spatial and temporal modulation of drug delivery resulting in alleviation of ALI.
Print ISSN: 0724-8741
Electronic ISSN: 1573-904X
Topics: Chemistry and Pharmacology
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Springer
Publication Date: 2018-03-14
Description: The lung is a preferential organ site for accumulation of lipophilic basic amine drugs, so-called pneumophilic drugs and belonging to various pharmacological classes, which can result in lung toxicity. In order to investigate the mechanism involved in such pulmonary accumulation of drugs, uptake of clonidine, used here as a prototypical basic amine drug, was characterized in cultured human lung cells. Clonidine accumulation in lung alveolar A549 cells was found to be temperature- and pH-dependent; it was saturable, with a Michaelis–Menten affinity constant (Km) value of 569.4 μM. Various pneumophilic drugs, including amitriptyline, verapamil, propranolol, chlorpromazine, imipramine, and quinidine, markedly cis -inhibited clonidine uptake in A549 cells, in a dose-dependent manner for at least some of them. They additionally trans -stimulated clonidine efflux from A549 cells, thus suggesting that they are substrates for the putative clonidine transporter. In addition to alveolar A549 cells, bronchial epithelial BEAS-2B cells as well as lung endothelial HULEC-5a cells were found to exhibit clonidine accumulation abrogated by amitriptyline, verapamil, and chlorpromazine. Taken together, these data likely provided evidence for carrier-mediated uptake of clonidine in human lung cells. This carrier, which remains to be molecularly identified, interacts with various pneumophilic drugs, suggesting that it may contribute to lung accumulation of these drugs in a notable way.
Print ISSN: 0028-1298
Electronic ISSN: 1432-1912
Topics: Medicine
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Springer
Publication Date: 2018-03-14
Description: Diabetic nephropathy is the leading cause of end-stage renal disease and is associated with high-cardiovascular risk and significant morbidity and mortality. The recent development of sodium-glucose cotransporter (SGLT) 2 inhibitors offers a new antidiabetic therapy via enhanced glucose excretion; however, the beneficial effect of these drugs on the development of type 2 diabetic overt nephropathy is still largely unclear. We examined the therapeutic effects of the SGLT2 inhibitor ipragliflozin on various diabetic symptoms and the progression of nephropathy in uninephrectomized type 2 diabetic mice, which exhibit not only typical diabetic symptoms, such as impaired insulin secretion, glucose intolerance, hyperglycemia, and obesity, but also overt nephropathy with decline in renal function. Diabetes was induced by intraperitoneal administration of nicotinamide (1000 mg/kg) and streptozotocin (150 mg/kg) to uninephrectomized high-fat diet-fed mice. Ipragliflozin (0.1–3 mg/kg) was orally administered to diabetic mice once daily for 4 weeks. Repeated administration of ipragliflozin improved diabetic symptoms, such as hyperglycemia and insulin resistance, via an increase in urinary glucose excretion. In addition, ipragliflozin attenuated albuminuria/proteinuria and the decline in renal function, and improved renal injury, including glomerulosclerosis and interstitial fibrosis. Our results demonstrate that ipragliflozin improves various diabetic symptoms and delays development of diabetic nephropathy. Therefore, SGLT2 inhibitors could constitute a novel therapeutic target for the treatment of type 2 diabetes with overt nephropathy.
Print ISSN: 0028-1298
Electronic ISSN: 1432-1912
Topics: Medicine
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Publication Date: 2018-03-14
Description: Endothelin-1 (ET-1), a potent vasoconstrictor normally active in maintaining vascular tone, may mediate significant pathogenic effects, contributing to several serious diseases when aberrantly expressed or regulated. The present study evaluates the capacity of ET-1 to affect endothelin-1-associated hypertrophic activity and decreased expression of heme oxygenase-1 by H9c2 rat cardiomyoblasts in vitro, corresponding to in vivo processes underlying cardiovascular diseases (CVDs). Beta estradiol (β-E) is tested for its capacity to alter the effects of ET-1. H9c2 cells, cultured 48 h, were stimulated with 100–10,000 nM of ET-1 and evaluated for changes in cell size, cell viability, and expression of the cytoprotective heat shock protein heme oxygenase-1 (HO-1), with 200 nM of β-E included in selected cultures to evaluate its effect on ET-1-mediated changes. The application of 100 to 10,000 nM of ET-1 resulted in a significant increase in average cell size and decreases in both cell viability and HO-1 protein content ( p  〈 0.05). Moreover, 200 nM of β-E was observed to significantly counteract these effects by cardiomyoblasts stimulated with 1000 nM of ET-1 ( p  〈 0.05). Sprague-Dawley rats treated intravenously with 1000 ng/kg of ET-1 demonstrated reduced HO-1 expression in peripheral blood and left ventricular tissue, which was counteracted by injection of 200 ng/kg β-E—demonstrating a possible correspondence between in vitro and in vivo effects. An outcome of particular value for clinical use of β-E, in the management of cardiac hypertrophy, is the observed capacity of the drug to abate ET-1-mediated suppression of HO-1 expression. It has been previously demonstrated that HO-1 inducers exhibit potent cardioprotective properties, thus offering the promise of combining them with β-E, allowing lower effective dosage of the drug and concomitantly lower adverse side effects associated with its clinical use. Major findings of this investigation are that pretreatment of cardiomyoblasts with β-E inhibited their hypertrophic response to ET-1 and counteracts the decrease of cell viability. These effects were associated with a restoration of HO-1 protein expression in both under in vitro and in vivo conditions.
Print ISSN: 0028-1298
Electronic ISSN: 1432-1912
Topics: Medicine
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Publication Date: 2018-03-14
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
Topics: Medicine
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Springer
Publication Date: 2018-03-14
Description: Background Cancer patients frequently suffer from physical and psychosocial impairments due to their disease and its treatment. Psychooncology (PO) can help to cope with stress resulting from outpatient radiotherapy (RT) treatment. There are currently few data regarding patients’ wishes for PO support. The aim of this study was to investigate the number of patients with a wish for PO, treatment paths, and predictors of the wish for PO among cancer patients at the beginning of RT. Methods The results of routine psychological stress screening (Hornheide screening instrument; cut-off  ≥ 4) of 944 cancer patients between 2015 and 2017 were analyzed in a retrospective cross-sectional study. Predictors for a wish for PO support were identified by stepwise binary logistic regression, in which sociodemographic and treatment data were included in addition to the screening items. Results Around 20% of patients had above-average stress levels and 13% expressed a wish for PO support (participation rate was approximately 55%). Low emotional wellbeing (OR = 11.3) and lack of social support (OR = 9.4) were strong predictors for this treatment wish. Among patients with pancreatic cancer, head and neck tumors, and hematologic disease, there was a substantial difference between the degree of psychological stress and the wish for treatment. Patients with urological (23.5%) and lung tumors (20.9%) most frequently expressed a wish for PO support. Conclusion Patient-reported psychosocial problems were better predictors of a wish for PO support than sociodemographic or clinical data. Stress screening should thus be implemented in clinical routine.
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
Topics: Medicine
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Springer
Publication Date: 2018-03-14
Electronic ISSN: 1432-2307
Topics: Medicine
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Springer
Publication Date: 2018-03-14
Description: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) frequently harbors dense lymphocytic infiltration, suggesting a specific microenvironment allowing coexistence with tumor immunity. CD47, which mediates the “do not eat me” signal in innate immunity, is also important in adaptive anti-tumor immunity. We investigated the significance of CD47 in EBVaGC compared with EBV-negative gastric cancer and the correlation with various immune cells. By immunohistochemistry of CD47, high, low, and negative expression was observed in 24, 63, and 12% of EBVaGC ( n  = 41), while 11, 49, and 39% of EBV-negative gastric cancer ( n  = 262), respectively, indicating that high expression of CD47 in cancer cells was significantly frequent and increased in EBVaGC ( P  = 0.043). In contrast to EBV-negative gastric carcinoma in which no significant correlation was observed between CD47 and survival, high expression of CD47 correlated significantly with worse disease-specific survival ( P  = 0.011) and overall survival ( P  = 0.013) in EBVaGC. To further clarify the role of CD47 expression in EBVaGC, digital image analysis of immune cell infiltration revealed that high CD47 expression was correlated with a lower ratio of CD8 + /Foxp3 + T cells ( P  = 0.021), a sensitive indicator of tumor immunity. Thus, CD47 lowers anti-tumor immunity in EBVaGC by finely tuning profile of infiltrating T cells, suggesting that CD47 is an additional target for cancer immunotherapy against this virus-driven gastric cancer.
Electronic ISSN: 1432-2307
Topics: Medicine
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Publication Date: 2018-03-14
Description: Background External ventricular drain (EVD) insertion is a common neurosurgical procedure with a significant risk of ventriculostomy-associated infections (VAIs), other morbidities and mortality. Several risk factors have been identified but their effect is unclear. Objective Our primary objective was to assess whether recurrent EVD sampling increased the risk of VAIs. The secondary objective was to explore the effect of sampling frequency, duration of EVD stay, presence of cerebrospinal fluid leak and concurrent infections. Methods Ours was a retrospective, single-centre, age-matched, case control study of 83 patients and 249 controls who underwent EVD insertion between 1 January 2010 – 31 December 2016. Patients with primary CNS infections, age under 1 year and death within 5 days of EVD insertion were excluded. Blinded abstractors collected all patient data through the electronic patient record system and regression analysis was used to compare the two groups. Results Sampling the EVD more than once did not increase the risk of infection (OR 0.47, 95% CI 0.27–0.83, p  = 0.01). Risk factors significantly associated with VAI included CSF leak (OR 2.06, 95% CI 1.16–3.67, p  = 0.01), concurrent infection (OR 1.85, 95% CI 1.09–3.16, p  = 0.02), and an EVD duration of 〉10 days (OR 2.28, 95% CI 1.24–4.18, p  = 0.01). Conclusion Our findings do not support the notion that increased sampling of EVDs is associated with a higher risk of VAI. CSF leaks, concurrent infection and long-term EVDs are also statistically significant risk factors for infection.
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
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Springer
Publication Date: 2018-03-14
Description: New drug development is both resource and time intensive, where later clinical stages result in significant costs. We analyze recent late-stage failures to identify drugs where failures result from inadequate scientific advances as well as drugs where we believe pitfalls could have been avoided. These can be broadly classified into two categories: 1) where science is mature and the failures can be avoided through rigorous and prospectively determined decision-making criteria, scientific curiosity, and discipline to follow up on emerging findings; and 2) where problems encountered in Phase 3 failures cannot be explained at this time, as the science is not sufficiently advanced and companies/investigators need to recognize the possibility of deficiency of our knowledge. Through these case studies, key themes critical for successful drug development emerge—understanding the therapeutic pathway including receptor and signaling biology, pharmacological responses related to safety and efficacy, pharmacokinetics of the drug and exposure at target site, optimum dose, and dosing regimen; and identification of patient sub-populations likely to respond and will have a favorable benefit-risk profile, design of clinical trials, and a quantitative framework that can guide data-driven decision making. It is essential that the right studies are conducted early in the development process to answer the key questions, with the emphasis on learning in the early stages of development, whereas Phase 3 should be reserved for confirming the safety and efficacy. Utilization of innovative technology in identifying patients based on molecular signature of their disease, rapid assessment of pharmacological response, mechanistic modeling of emerging data, seamless operational processes to reduce start-up and wind-down time for clinical trials through use of electronic health records and data mining, and development of novel and objective clinical efficacy endpoints are some concepts for improving the success rate.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Publication Date: 2018-03-14
Description: We present an insert-based approach to fabricate scalable and multiplexable microfluidic devices for 3D cell culture and integration with downstream detection modules. Laser-cut inserts with a layer of electrospun fibers are used as a scaffold for 3D cell culture, with the inserts being easily assembled in a 3D-printed fluidic device for flow-based studies. With this approach, the number and types of cells (on the inserts) in one fluidic device can be customized. Moreover, after an investigation (i.e., stimulation) under flowing conditions, the cell-laden inserts can be removed easily for subsequent studies including imaging and cell lysis. In this paper, we first discuss the fabrication of the device and characterization of the fibrous inserts. Two device designs containing two (channel width = 260 μm) and four (channel width = 180 μm) inserts, respectively, were used for different experiments in this study. Cell adhesion on the inserts with flowing media through the device was tested by culturing endothelial cells. Macrophages were cultured and stimulated under different conditions, the results of which indicate that the fibrous scaffolds under flow conditions result in dramatic effects on the amount and kinetics of TNF-α production (after LPS stimulation). Finally, we show that the cell module can be integrated with a downstream absorbance detection scheme. Overall, this technology represents a new and versatile way to culture cells in a more in vivo fashion for in vitro studies with online detection modules. Graphical abstract This paper describes an insert-based microfluidic device for 3D cell culture that can be easily scaled, multiplexed, and integrated with downstream analytical modules.
Print ISSN: 1618-2642
Topics: Chemistry and Pharmacology
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Springer
Publication Date: 2018-03-05
Description: In the published article, the author B. Babbitt was cited as affiliation 9, but should have been cited as affiliation 2. In addition, there are 2 errors in the affiliations. The correct affiliations are shown in this erratum.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Publication Date: 2018-03-05
Description: Low accumulation in tumor sites and slow intracellular drug release remain as the obstacles for nanoparticles to achieve effective delivery of chemotherapeutic drugs. In this study, multifunctional micelles were designed to deliver doxorubicin (Dox) to tumor sites to provide more efficient therapy against hepatic carcinoma. The micelles were based on pH-responsive carboxymethyl chitosan (CMCh) modified with a reactive oxygen species (ROS)-responsive segment phenylboronic acid pinacol ester (BAPE) and an active targeted ligand CD147 monoclonal antibody. The Dox-loaded micelles provided rapid and complete drug release in pH 5.3 incubation conditions with 1 mM H 2 O 2 . In addition, an in vitro cell uptake study revealed that CD147 modification significantly enhanced cellular internalization due to the high affinity to CD147 receptors, which are overexpressed on tumor cells. An in vivo study revealed that CD147-modified micellar formulations exhibited high accumulation in tumor sites and markedly enhanced antiproliferation effects with fewer side effects than other formulations. In conclusion, this CD147 receptor targeted delivery system with ROS/pH dual sensitivity provides a promising strategy for the treatment of hepatic carcinoma.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Springer
Publication Date: 2018-03-05
Description: The citation of the author name “Ah-Ng Tony Kong” in PubMed is not the author’s preference. Instead of “Kong AT”, the author prefers “Kong AN”.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Springer
Publication Date: 2018-03-05
Description: The development of novel therapies that can harnass the immune system to eradicate cancer is an area of intensive research. Several new biopharmaceuticals that target the immune system rather than the tumor itself have recently been approved and fundamentally transformed treatment of many cancer diseases. This success has intensified the search for new targets and modalities that could be developed as even more effective therapeutic agents either as monotherapy or in combination. While great benefits of novel immunotherapies in oncology are evident, the safety of these therapies has to also be addressed as their desired pharmacology, immune activation, can lead to “exaggerated” effects and toxicity. This review is focused on the unique challenges of the nonclinical safety assessment of monoclonal antibodies that target immune checkpoint inhibitors and costimulatory molecules. This class of molecules represents several approved drugs and many more drug candidates in clinical development, for which significant experience has been gained. Their development illustrates challenges regarding the predictivity of the animal models for assessing safety and setting starting doses for first-in-human trials as well as the translatability of nonclinical in vitro and in vivo data to the human findings. Based on learnings from the experience to date, factors to consider and novel approaches to explore are discussed to help address the unique safety issues of immuno-oncology drug development.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Publication Date: 2018-03-05
Description: Intranasal administration could be an attractive alternative route of administration for the delivery of drugs to the central nervous system (CNS). However, there are always doubts about the direct transport of therapeutics from nasal cavity to the CNS since there are only limited studies on the understanding of direct nose-to-brain transport. Therefore, this study aimed to (1) investigate the existence of nose-to-brain transport of intranasally administered HIV-1 replication inhibitor DB213 and (2) assess the direct nose-to-brain transport of unbound HIV-1 replication inhibitor DB213 quantitatively by a pharmacokinetic approach. Plasma samples were collected up to 6 h post-dosing after administration via intranasal or intravenous route at three bolus doses. In the brain-uptake study, the plasma, whole brain, and cerebrospinal fluid (CSF) were sampled between 15 min and 8 h post-dosing. All samples were analyzed with LC/MS/MS. Plasma, CSF, and brain concentration versus  time profiles were analyzed with nonlinear mixed-effect modeling. Structural model building was performed by NONMEM (version VII, level 2.0). Intranasal administration showed better potential to deliver HIV-1 replication inhibitor DB213 to the brain with 290-fold higher brain to plasma ratio compared with intravenous administration. Based on that, a model with two absorption compartments (nose-to-systemic circulation and nose-to-brain) was developed and demonstrated 72.4% of total absorbed unbound HIV-1 replication inhibitor DB213 after intranasal administration was transported directly into the brain through nose-to-brain pathway.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Publication Date: 2018-03-05
Description: Despite the improvements in drug screening, high levels of drug attrition persist. Although high-throughput screening platforms permit the testing of compound libraries, poor compound efficacy or unexpected organ toxicity are major causes of attrition. Part of the reason for drug failure resides in the models employed, most of which are not representative of normal organ biology. This same problem affects all the major organs during drug development. Hepatotoxicity and cardiotoxicity are two interesting examples of organ disease and can present in the late stages of drug development, resulting in major cost and increased risk to the patient. Currently, cell-based systems used within industry rely on immortalized or primary cell lines from donated tissue. These models possess significant advantages and disadvantages, but in general display limited relevance to the organ of interest. Recently, stem cell technology has shown promise in drug development and has been proposed as an alternative to current industrial systems. These offerings will provide the field with exciting new models to study human organ biology at scale and in detail. We believe that the recent advances in production of stem cell-derived hepatocytes and cardiomyocytes combined with cutting-edge engineering technologies make them an attractive alternative to current screening models for drug discovery. This will lead to fast failing of poor drugs earlier in the process, delivering safer and more efficacious medicines for the patient.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Publication Date: 2018-03-05
Description: Simvastatin (Sim), a lipid-lowering drug has been studied in chronic neuroinflammation associated with degenerative brain disorders due to its potential protective properties against inflammatory reaction, oxidative damage, neuronal dysfunction, and death. Meanwhile, potential application of Sim in neuroinflammation will require a suitable delivery system that can overcome notable challenges pertaining to poor blood–brain barrier (BBB) permeability and side/off-target effects. Herein, we engineered and characterized nano-sized polymersomes loaded with Sim (Sim-Ps) using PEG-PdLLA (methoxy polyethylene glycol-poly( d , l ) lactic acid) diblock co-polymers. Studies in BV2 microglia indicated that Sim-Ps was superior to Sim alone in suppressing nitric oxide (NO) and proinflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) secretion against LPS activation. The effectiveness of Sim-Ps as compared with Sim alone, in attenuating NO and cytokine production by activated BV2 cells can be attributed to (a) colloidal stability of the delivery platform, (b) protracted release of biologically active Sim, and (c) particulate internalization coupled with enhanced Sim exposure to BV2 cells. Intranasal delivery in BALB/c mice demonstrated enhanced brain distribution with increasing time after administration. Overall data demonstrated suitability of PEG-PdLLA polymersomes in Sim delivery for potential application in treating neuroinflammation.
Electronic ISSN: 1550-7416
Topics: Chemistry and Pharmacology
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Publication Date: 2018-03-05
Description: Background Brain metastases from hepatocellular carcinoma (HCC) are rare, but their incidence is increasing because of developments in recent therapeutic advances. The purpose of this study was to investigate the characteristics of brain metastases from HCC, to evaluate the predictive factors, and to assess the efficacy of gamma knife surgery (GKS). Method A retrospective study was performed on patients with brain metastases from HCC who were treated at Tokyo Gamma Unit Center from 2005 to 2014. Results Nineteen patients were identified. The median age at diagnosis of brain metastases was 67.0 years. Fifteen patients were male and four patients were female. Six patients were infected with hepatitis B virus (HBV). Two patients were infected with hepatitis C virus (HCV). Eleven patients were not infected with HBV or HCV. The median interval from the diagnosis of HCC to brain metastases was 32.0 months. The median number of brain metastases was two. The median Karnofsky performance score at first GKS was 70. The median survival time following brain metastases was 21.0 weeks. Six-month and 1-year survival rates were 41.2 and 0%, respectively. One month after GKS, no tumor showed progressive disease. The HBV infection (positive vs. negative) was significantly associated with survival according to univariate analysis ( p  = 0.002). Conclusions The patients having brain metastases from HCC had poor prognosis and low performance state. Therefore, GKS is an acceptable option for controlling brain metastases from HCC because GKS is noninvasive remedy and local control is reasonable.
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Electronic ISSN: 0942-0940
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Publication Date: 2018-03-05
Print ISSN: 0001-6268
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Publication Date: 2018-03-05
Description: Background The aim of this study was to develop a minimal invasive complete spinal cord injury (SCI) minipig model for future research applications. The minipig is considered a translationally relevant model for SCI research. However, a standardized minimal invasive complete SCI model for pigs has not yet been established. Methods Adult Göttingen minipigs were anesthetized and placed in extended prone position. After initial computed tomography (CT) scan, the skin was incised, a needle placed in the epidural fatty tissue. Using the Seldinger technique, a guidewire and dilators were introduced to insert the balloon catheter to Th12. After confirmation of the level Th11/Th12, the balloon was inflated to 2 atm for 30 min. The severity of the lesion was followed by CT and by MRI, and by immunohistochemistry. Function was assessed at the motor and sensory level. Results Duration of procedure was about 60 min including the 30-min compression time. The balloon pressure of 2 atm was maintained without losses. The lesion site was clearly discernible and no intradural bleeding was observed by CT. Neurological assessments during the 4-month follow-up time showed consistent, predictable, and stable neurological deficits. Magnetic resonance imaging analyses at 6 h and 4 weeks post SCI with final immunohistochemical analyses of spinal cord tissue underlined the neurological outcomes and proved SCI completeness. Conclusions We have established a new, minimal invasive, highly standardized, CT-guided spinal cord injury procedure for minipigs. All risks of the open surgery can be excluded using this technique. This CT-guided SC compression is an excellent technique as it avoids long surgery and extensive trauma and allows a feasible inter-animal comparison.
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Publication Date: 2018-03-05
Description: Background Wound healing impairment is a serious problem in surgical disciplines which may be associated with chronic morbidity, increased cost and patient discomfort. Here we aimed to investigate the relevance of bacterial colonisation on suture material using polymerase chain reaction (PCR) to detect and taxonomically classify bacterial DNA in patients with and without wound healing problems after routine neurosurgical procedures. Methods Repeat surgery was performed in 25 patients with wound healing impairment and in 38 patients with well-healed wounds. To determine the presence of bacteria, a 16S rDNA-based PCR detection method was applied. Fragments of 500 bp were amplified using universal primers which target hypervariable regions within the bacterial 16S rRNA gene. Amplicons were separated from each other by single-strand conformation polymorphism (SSCP) analysis, and finally classified using Sanger sequencing. Results PCR/SSCP detected DNA of various bacteria species on suture material in 10/38 patients with well-healed wounds and in 12/25 patients with wound healing impairment including Staphylococcus aureus , Staphylococcus epidermidis , Propionibacterium acnes and Escherichia coli . Microbiological cultures showed bacterial growth in almost all patients with wound healing impairment and positive results in PCR/SSCP (10/12), while this was the case in only one patient with a well-healed wound (1/10). Conclusions Colonisation of suture material with bacteria occurs in a relevant portion of patients with and without wound healing impairment after routine neurosurgical procedures. Suture material may provide a nidus for bacteria and subsequent biofilm formation. Most likely, however, such colonisation of sutures is not a general primer for subsequent wound infection.
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Publication Date: 2018-03-05
Description: Background Perineural spread (PNS) of pelvic cancer along the lumbosacral plexus is an emerging explanation for neoplastic lumbosacral plexopathy (nLSP) and an underestimated source of patient morbidity and mortality. Despite the increased incidence of PNS, these patients are often times a clinical conundrum—to diagnose and to treat. Building on previous results in modeling glioblastoma multiforme (GBM), we present a mathematical model for predicting the course and extent of the PNS of recurrent tumors. Methods We created three-dimensional models of perineurally spreading tumor along the lumbosacral plexus from consecutive magnetic resonance imaging scans of two patients (one each with prostate cancer and cervical cancer). We adapted and applied a previously reported mathematical model of GBM to progression of tumor growth along the nerves on an anatomical model obtained from a healthy subject. Results We were able to successfully model and visualize perineurally spreading pelvic cancer in two patients; average growth rates were 60.7 mm/year for subject 1 and 129 mm/year for subject 2. The model correlated well with extent of PNS on MRI scans at given time points. Conclusions This is the first attempt to model perineural tumor spread and we believe that it provides a glimpse into the future of disease progression monitoring. Every tumor and every patient are different, and the possibility to report treatment response using a unified scale—as “days gained”—will be a necessity in the era of individualized medicine. We hope our work will serve as a springboard for future connections between mathematics and medicine.
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Springer
Publication Date: 2018-03-05
Description: A 42-year-old man had an unstable Jefferson type IV atlas fracture with unilateral vertebral artery occlusion after a diving accident. We performed C1-ring reconstruction with a crosslink rod and C2 fixation to directly reduce the fracture fissure. Within 6 h, cerebellar hemisphere infarction developed. After decompressive craniectomy, duroplasty, and release of the vertebral artery occlusion caused by the transfixing rod, a postoperative computed tomography angiogram showed that blood flow in the right vertebral artery improved. We suggest cautiously inserting screws into the fractured C1 lateral mass and gently tightening the crosslink rod to prevent distal migration of a thrombus.
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
Topics: Medicine
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Springer
Publication Date: 2018-03-05
Description: Background Intraperitoneal pressure (IPP) counteracts the diversion of cerebrospinal fluid (CSF) from the cranial to the peritoneal compartment during ventriculoperitoneal shunting. Animal studies suggest that the intrinsic IPP exceeds the intraperitoneal hydrostatic pressure. The intrinsic IPP in mobile patients is relevant for shunt therapy, but data about it is not available. Methods The IPP was measured indirectly in 25 mobile subjects (13 female) by applying a standard intravesical pressure measurement technique. Measurements were carried out in reference to the navel (supine position) and the xiphoid (upright position). Results were adjusted for the intraperitoneal hydrostatic pressure and correlated afterward with general body measures. Results The corrected mean (SD) IPP measured in the supine position was 4.4 (4.5) cm H 2 O, and the mean (SD) upright IPP was 1.6 (7.8) cm H 2 O ( p  = 0.02). A positive correlation was found between the body mass index (BMI) and the IPP in the upright ( r  = 0.51) and supine ( r  = 0.65) body positions, and between the abdominal circumference and the IPP in the supine position ( r  = 0.63). Conclusions The intrinsic IPP in mobile subjects exceeds the intraperitoneal hydrostatic pressure. Thus, the intrinsic IPP counteracts the diversion of CSF into the peritoneal compartment. The intrinsic IPP is correlated with mobile patients’ general body measures.
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
Topics: Medicine
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Springer
Publication Date: 2018-03-05
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
Topics: Medicine
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• 80
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Springer
Publication Date: 2018-03-05
Description: The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2-expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared. Math2 + neurons also exhibited more rapid and severe cell loss in both in vitro and in vivo models of synucleinopathy. Toxicity resulting from PFF exposure was dependent on endogenous aSyn and could be attenuated by N -acetyl-cysteine through a glutathione-dependent process. Moreover, aSyn expression levels strongly correlate with relative vulnerability among hippocampal neuron subtypes of which Math2 + neurons contained the highest amount. Consistent with this, antisense oligonucleotide (ASO)-mediated knockdown of aSyn reduced the neuronal pathology in a time-dependent manner. However, significant neuroprotection was observed only with early ASO intervention and a substantial reduction of aSyn pathology, indicating toxicity occurs after a critical threshold of pathological burden is exceeded in vulnerable neurons. Together, our findings reveal considerable heterogeneity in endogenous aSyn levels among hippocampal neurons and suggest that this may contribute to the selective vulnerability observed in the context of synucleinopathies.
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
Topics: Medicine