bluuebunny/crossref_metadata_2025 huggingface dataset:
Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger
Authors: Piccirillo Silvia , Castaldo Pasqualina , Macrì Maria Loredana , Amoroso Salvatore , Magi Simona
Published: June 2018

In brain ischemia, reduction in oxygen and substrates affects mitochondrial respiratory chain and aerobic metabolism, culminating in ATP production impairment, ionic imbalance, and cell death. The restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury, giving rise to ischemia/reperfusion (I/R) injury. In this setting, the imbalance of brain bioenergetics induces important metabolic adaptations, including utilization of alternative energy sources, such as glutamate. Although glutamate has long been considered as a neurotoxin, it can also be used as intermediary metabolite for ATP synthesis, and both the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino-acid transporters (EAATs) are essential in this pathway. Here we analyzed the role of NCX in the potential of glutamate to improve metabolism and survival of neuronal cells subjected to hypoxia/reoxygenation (H/R). In SH-SY5Y neuroblastoma cells differentiated into a neuron-like state, H/R produced a significant cell damage, a decrease in ATP cellular content, and intracellular Ca2+ alterations. Exposure to glutamate at the onset of the reoxygenation phase attenuated H/R-induced cell damage and evoked a significant raise in intracellular ATP levels. Furthermore, we found that in H/R cells NCX reverse-mode activity was reduced, and that glutamate limited such reduction. All the effects induced by glutamate supplementation were lost when cells were transfected with small interfering RNA against NCX1 and EAAT3, suggesting the need of a specific functional interplay between these proteins for glutamate-induced protection. Collectively, our results revealed the potential beneficial effect of glutamate in an in vitro model of H/R injury and focused on the essential role exerted by NCX1. Although preliminary, these findings could be a starting point to further investigate in in vivo systems such protective effect in ischemic settings, shedding a new light on the classical view of glutamate as detrimental factor.
Activated platelets induce MLKL-driven neutrophil necroptosis and release of neutrophil extracellular traps in venous thrombosis
Authors: Nakazawa Daigo , Desai Jyaysi , Steiger Stefanie , Müller Susanne , Devarapu Satish Kumar , Mulay Shrikant R. , Iwakura Takamasa , Anders Hans-Joachim
Published: June 2018

Venous thromboembolic (VTE) disease, often manifesting as deep vein thrombosis or pulmonary embolism, involves clot formation consisting of blood cells and platelets locked in plasma protein and chromatin networks. The latter derives from neutrophil extracellular traps released by dying neutrophils; however, the molecular mechanisms of neutrophil death in VTE remains unknown. We speculated that mixed lineage kinase-like (MLKL)-driven neutrophil necroptosis contributes to VTE. Indeed, human inferior venous cava thrombus material stained positive for phosphorylated MLKL, the activated version of MLKL that executes necroptotic cell death. In mice, MLKL immunostaining showed co-localization of MLKL with citrullinated histone H3, a marker of neutrophil extracellular trap (NET) formation. These data provide indirect support for a role of MLKL-mediated necroptosis. As a functional proof, both the stabilizer of receptor-interacting protein kinase-1 (RIPK1) and necroptosis inhibitor necrostatin-1s as well as genetic deficiency of MLKL partially prevented clot formation upon inferior vena cava ligation in mice. In both experiments terminal deoxynucleotidyl transferase dUTP nick-end labeling, RIPK3, and citrullinated histone H3+ areas were markedly reduced within the remnant thrombus. In vitro, thrombin-activated platelets induced cell death and NET formation in human neutrophils, which was inhibited by necrostatin-1s treatment. Necrostatin-1s and necrosulfonamide also inhibited neutrophil–platelet aggregate formation induced by tumor necrosis factor-α but had no effect on platelet activation itself. We conclude that in VTE, activated platelets, and possibly other triggers, induce neutrophil necroptosis, a process contributing to clot formation by releasing chromatin in the extracellular space.
Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers
Authors: Yu Miaorong , Xu Lu , Tian Falin , Su Qian , Zheng Nan , Yang Yiwei , Wang Jiuling , Wang Aohua , Zhu Chunliu , Guo Shiyan , Zhang XinXin , Gan Yong , Shi Xinghua , Gao Huajian
Published: June 2018

To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.
Glucose starvation induces LKB1-AMPK-mediated MMP-9 expression in cancer cells
Authors: Endo Hitoshi , Owada Satoshi , Inagaki Yutaka , Shida Yukari , Tatemichi Masayuki
Published: June 2018

Cancer cells utilise the glycolytic pathway to support their rapid growth and proliferation. Since cells in most solid tumours are subjected to severe microenvironmental stresses including low nutrient and oxygen availability, such cancer cells must develop mechanisms to overcome these unfavourable growth conditions by metabolic adaptation. Although the liver kinase B1 (LKB1)-adenosine monophosphate-activated kinase (AMPK) signalling pathway plays a pivotal role in maintaining energy homeostasis under conditions of metabolic stress, the role of LKB1-AMPK signalling in aiding cancer cell survival and in malignant tumours has not yet been fully elucidated. We show that glucose starvation promotes cancer cell invasiveness and migration through LKB1-AMPK-regulated MMP-9 expression. Most intriguingly, triggering the LKB1-AMPK signalling pathway by glucose starvation-induced oxidative stress facilitates selective autophagy, which in turn enhances Keap1 degradation and the subsequent activation of Nrf2. Following this, Nrf2 regulates the transactivation of MMP-9 via Nrf2 binding sites in the promoter region of the MMP-9 gene. These mechanisms also contribute to the suppression of excessive oxidative stress under glucose starvation, and protect against cell death. Our data clearly shows that LKB1-AMPK signalling not only maintains energy and oxidative stress homeostasis, but could also promote cancer progression during metabolic stress conditions by MMP-9 induction.
An exciton-polariton bolometer for terahertz radiation detection
Authors: Paschos G. G. , Liew T. C. H. , Hatzopoulos Z. , Kavokin A. V. , Savvidis P. G. , Deligeorgis G.
Published: June 2018

We experimentally investigate the feasibility of a bolometric device based on exciton-polaritons. Initial measurements presented in this work show that heating – via thermal expansion and bandgap renormalization – modifies the exciton-polariton propagation wavevector making exciton-polaritons propagation remarkably sensitive to thermal variations. By theoretical simulations we predict that using a single layer graphene absorbing layer, a THz bolometric sensor can be realized by a simple exciton-polariton ring interferometer device. The predicted sensitivity is comparable to presently existing THz bolometric devices with the convenience of being a device that inherently produces an optical signal output.
Graphene oxide polarizes iNKT cells for production of TGFβ and attenuates inflammation in an iNKT cell-mediated sepsis model
Authors: Lee Sung Won , Park Hyun Jung , Van Kaer Luc , Hong Suklyun , Hong Seokmann
Published: June 2018

Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d-dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by α-galactosylceramide (α-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of α-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate-like cells, including DCs, macrophages, NK cells, and γδ T cells. Such effects of GO on α-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFβ production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against α-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an α-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from α-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy.
Identification of genes underlying the enhancement of immunity by a formula of lentinan, pachymaran and tremelia polysaccharides in immunosuppressive mice
Authors: Luo Xia , Huang Shaowei , Luo Shuang , Liao Haifeng , Wang Yuanyuan , Deng Xiangliang , Ma Fangli , Ma Chung Wah , Zhou Lian
Published: June 2018

The efficacy of polysaccharides is widespread, especially in immune regulation. However, the genetic basis of the changes in polysaccharides regulating immunity is unclear. To obtain genome-wide insights into transcriptome changes and regulatory networks, we designed a polysaccharide formula, comprising lentinan, pachymaran and tremelia, to increase the availability of their optimized active sites. In this case, we focused on a model of immunosuppression to investigate genes by digital gene expression (DGE) tag profiling in T and B cells. These genes were further validated by qRT-PCR and Western blot experiments. Consequently, polysaccharide formula treatment helped to recover the expression of immune-related genes, including CADM1, CCR2, IGLL1, LIGP1, and FCGR3, FCGR2 in B cells, as well as S100A8, S100A9, ChIL3, MMP8 and IFITM3 in T cells. These results suggest that treatment with polysaccharides improves the immunity of immunosuppressive mice by regulating genes associated with T and B cell functions.
Direct evidence of a low barrier hydrogen bond in the catalytic triad of a Serine protease
Authors: Agback Peter , Agback Tatiana
Published: June 2018

Serine proteases are one of the largest groups of enzymes, found in both eukaryotes and prokaryotes, and are responsible for many different functions. The detailed information about the hydrogen-bonds in the catalytic triad (Asp…His…Ser) of these enzymes is of importance in order to fully understand the mechanism of action. The aspartate of the triad is hydrogen bonded to the histidine but the exact nature of this bond has been under discussion for some time. It is either a common short ionic hydrogen bond (SIHB) or a delocalized low barrier hydrogen bond (LBHB) were the hydrogen bond is shorter. So far, the evidence for LBHB in proteins have not been conclusive. Here we show clear NMR evidence that LBHB does exist in NS3, a serine protease from Dengue. The one bond coupling constant between the hydrogen and nitrogen was shown to be only 52 Hz instead of the usual 90 Hz. This together with a 1H chemical shift of 19.93 ppm is evidence that the hydrogen bond distance between His and Asp is shorter than for SIHB. Our result clearly shows the existence of LBHB and will help in understanding the mechanism of the catalytic triad in the important group of serine proteases.
Monomolecular tetrahelix of polyguanine with a strictly defined folding pattern
Authors: Kankia Besik
Published: June 2018

The G3TG3TG3TG3 (G3T) sequence folds into a monomolecular quadruplex with all-parallel G3 segments connected to each other by chain-reversal loops. The homopolymer consisting of n number of G3T domains directly conjugated to each other folds into an uninterrupted and unusually stable polymer, tetrahelical monomolecular DNA (tmDNA). It was demonstrated that the tmDNA architecture has strong potential in nanotechnologies as highly programmable building material, high affinity coupler and the driving force for endergonic reactions. Here, we explore capability of analogous DNA sequences (i.e., monomolecular quadruplexes with G2 or G4 segments) to construct tmDNA architecture. The study demonstrates that tmDNA can have only one building pattern based on a quadruplex domain with three G-tetrads and single-nucleotide loops, G3N (N = G, A, C and T); all other domains demonstrate antiparallel topologies unsuitable for tmDNA. The present study also suggests that polyguanine is capable of tmDNA formation with strictly defined building pattern; G3 segments connected to each other by chain-reversal G-loops. These findings can have significant impact on (i) DNA nanotechnologies; (ii) structure prediction of G-rich sequences of genome; and (iii) modeling of abiogenesis.
Correction: Corrigendum: Deciphering the function of the CNGB1b subunit in olfactory CNG channels
Authors: Nache Vasilica , Wongsamitkul Nisa , Kusch Jana , Zimmer Thomas , Schwede Frank , Benndorf Klaus
Published: June 2018

Scientific Reports 6; Article number: 29378; published online: 11 July 2016; updated: 28 June 2018 The Acknowledgements section in this Article is incomplete. “We like to thank to K. Schoknecht, S. Bernhardt, and A. Kolchmeier for excellent technical assistance. This work was supported by grants of the Deutsche Forschungsgemeinschaft to K.
A novel mechanism for user-friendly and self-activated microdroplet generation capable of programmable control
Authors: Jiang Yangyang , Du Lin , Li Yuanming , Mu Quanquan , Cui Zhongxu , Zhou Jia , Wu Wenming
Published: June 2018

The real-time continuous-flow PCR inside a 3D spiral microchannel is realized by a novel self-activated microdroplet generation/transport mechanism.
Design concepts in absorbance optical systems for analytical ultracentrifugation
Authors: Pearson Joseph , Hofstetter Marcel , Dekorsy Thomas , Totzeck Michael , Cölfen Helmut
Published: June 2018

Analytical ultracentrifugation is a powerful technique for analyzing particles in solution, and has proved valuable for a wide range of applications in chemistry, biochemistry and material sciences for many years.
ATR-FTIR spectroscopy with equidistant combination PLS method applied for rapid determination of glycated hemoglobin
Authors: Han Yun , Pan Tao , Zhou Huihui , Yuan Rui
Published: June 2018

A rapid quantification method of glycated hemoglobin (HbA1c) is proposed based on ATR-FTIR spectroscopy in human hemolysate samples.
An arene-tethered silylene ligand enabling reversible dinitrogen binding to iron and catalytic silylation
Authors: Bai Yunping , Zhang Jianying , Cui Chunming
Published: June 2018

A silylene–iron(0) dinitrogen complex enabled the catalytic silylation of N2with high activity.
Sustainable hydrophobic terpene-based eutectic solvents for the extraction and separation of metals
Authors: Schaeffer Nicolas , Martins Mónia A. R. , Neves Catarina M. S. S. , Pinho Simão P. , Coutinho João A. P.
Published: June 2018

Sustainable hydrophobic eutectic solvents, composed of low-priced and biodegradable terpenes and fatty acids, were used for the extraction and separation of Cu(ii) from other transition metals in mildly acidic solutions.
Intramolecular strong electronic coupling in a discretely H-aggregated phthalocyanine dimer connected with a rigid linker
Authors: Yamada Yasuyuki , Nawate Katsuhiko , Maeno Tomoaki , Tanaka Kentaro
Published: June 2018

This is the first example of a discrete dimer of phthalocyanines in an H-aggregate form. Intramolecular strong electronic coupling was observed between the phthalocyanines electrochemically.
Elucidating mysteries of phase-segregated membranes: mobile-lipid recruitment facilitates pores’ passage to the fluid phase
Authors: López Martí Jesús M. , English Niall J. , Del Pópolo Mario G.
Published: June 2018

Transmembrane pores created in liquid-ordered domains of phase segregated membranes migrate spontaneously to the liquid-disordered phase, via ‘recruitment’ of unsaturated lipids to the pore's rim.
Quantifying vapor transfer into evaporating ethanol drops in a humid atmosphere
Authors: Kita Yutaku , Okauchi Yuya , Fukatani Yuki , Orejon Daniel , Kohno Masamichi , Takata Yasuyuki , Sefiane Khellil
Published: June 2018

A simultaneous evaporation and water intake empirical model for evaporation of organic solvent ethanol drops.
Electro-analytical investigation of potential induced degradation in mc-silicon solar cells: case of sodium ion induced inductive loop
Authors: Purohit Zeel , Verma Deepak , Tripathi Brijesh
Published: June 2018

Potential induced degradation of the shunt type (PID-s) in multi-crystalline silicon (mc-Si) solar cells is becoming critical for performance reduction of solar panels in large scale photovoltaic (PV) power plants.
Unveiling the complex vibronic structure of the canonical adenine cation
Authors: Zhao Hong Yan , Lau Kai-Chung , Garcia Gustavo A. , Nahon Laurent , Carniato Stéphane , Poisson Lionel , Schwell Martin , Al-Mogren Muneerah Mogren , Hochlaf Majdi
Published: June 2018

Adenine, a DNA base, exists as several tautomers and isomers that are closely lying in energy and that may form a mixture upon vaporization of solid adenine.
Dual responsive salen-type Schiff bases for the effective detection of l-arginine via a static quenching mechanism
Authors: Mohan Nithya , Sreejith S. S. , Begum P. M. Sabura , Kurup M. R. Prathapachandra
Published: June 2018

The effect of substituents of salen Schiff bases on the detection of l-arginine via a static quenching mechanism is discussed.
An efficient iodine pentoxide-triggered iodocarbocyclization for the synthesis of iodooxindoles in water
Authors: Zhang Ming-Zhong , Wang Xin , Gong Ming-Ying , Chen Lin , Shi Wen-Bing , He Shu-Hua , Jiang Yong , Chen Tieqiao
Published: June 2018

highly efficient iodine pentoxide-triggered iodocarbocyclization for the synthesis of iodooxindoles has been established.
Effect of copolymer sequence on structure and relaxation times near a nanoparticle surface
Authors: Trazkovich Alex J. , Wendt Mitchell F. , Hall Lisa M.
Published: June 2018

Copolymer sequence affects the size and dynamics of the interphase region around a nanoparticle.
Engineering nanoporous Ag/Pd core/shell interfaces with ultrathin Pt doping for efficient hydrogen evolution reaction over a wide pH range
Authors: Yang C. , Lei H. , Zhou W. Z. , Zeng J. R. , Zhang Q. B. , Hua Y. X. , Xu C. Y.
Published: June 2018

The rational design and fabrication of highly efficient and durable all-pH catalysts for sustainable electrochemical hydrogen production are of critical importance to building renewable energy systems for the future.
A novel epoxy resin-based cathode binder for low cost, long cycling life, and high-energy lithium–sulfur batteries
Authors: Yan Longlong , Gao Xiguang , Wahid-Pedro Farihah , Ernest Quinn Jesse Thomas , Meng Yuezhong , Li Yuning
Published: June 2018

An epoxy resin PEI–ER formed by in situ reaction between an epoxide compound and polyethylenimine (PEI) is used as a new cathode binder for lithium–sulfur (Li–S) batteries.
NiFe LDH nanodots anchored on 3D macro/mesoporous carbon as a high-performance ORR/OER bifunctional electrocatalyst
Authors: Wang Wang , Liu Yucheng , Li Jun , Luo Jin , Fu Lei , Chen Shengli
Published: June 2018

Carbon defects tune the formation of NiFe LDH nanodots confined in the mesopores of a macro–mesoporous carbon substrate, forming a hybrid electrocatalyst with excellent bifunctional performance for oxygen evolution and reduction reactions.
Evaluation of Linguistic Markers of Word-Finding Difficulty and Cognition in Parkinson's Disease
Authors: Smith Kara M. , Ash Sharon , Xie Sharon X. , Grossman Murray
Published: June 2018

Purpose

Early cognitive symptoms such as word-finding difficulty (WFD) in daily conversation are common in Parkinson's disease (PD), but studies have been limited by a lack of feasible, quantitative measures. Linguistic analysis, focused on pauses in speech, may yield markers of impairment of cognition and communication in PD. The objective of this study was to evaluate the relationship of linguistic markers in semistructured speech to WFD symptoms and cognitive function in PD.

Method

Speech recordings of description of the Cookie Theft picture in 53 patients with PD without dementia and 23 elderly controls were analyzed with Praat software. Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005), category naming fluency, and confrontation naming tests were administered. Questionnaires rating WFD symptoms and cognitive instrumental activities of daily living were completed. We determined the relationships between (a) pause length and location, (b) MoCA score, and (c) WFD symptoms, using Pearson's correlations and multivariate regression models.

Results

Compared with controls, patients with PD had more pauses within utterances as well as fewer words per minute and a lower percentage of well-formed sentences. Pauses within utterances differed significantly between PD–mild cognitive impairment and normal cognition (
p
< .001). Words per minute and percentage of well-formed sentences were predictive of MoCA in multivariate regression models. Pauses before verbs were associated with patient-reported severity of WFD symptoms (
p
= .006).

Conclusions

Linguistic markers including pauses within utterances distinguish patients with PD with mild cognitive symptoms from elderly controls. These markers are associated with global cognitive function before the onset of dementia. Pauses before verbs and grammatical markers may index early cognitive symptoms such as WFD that may interfere with functional communication.

Supplemental Material

https://doi.org/10.23641/asha.6615401
Suchtprobleme unter Flüchtlingen und Migranten in Griechenland
Authors: Nikolaou Kakia
Published: June 2018

Der Flüchtlingsstatus verstärkt die Vulnerabilität höchst gefährdeter Menschen, die Pre-Migrations-Traumata und Post-Migrations-Stress ausgesetzt sind. Die Auswirkungen des Migrationsstresses spiegeln sich wieder in der Entwicklung von psychischen Störungen, besonders von posttraumatischen Stressstörungen, Angst und Depression, wodurch die Gefahr für Alkohol- und Drogenkonsum erhöht wird. In Griechenland kommen noch die Auswirkungen der ökonomischen und humanistischen Krise hinzu. Flüchtlinge auf den griechischen Inseln müssen sich an den Empfangs- und Identifizierungszentren einen komplizierten und langwierigen Prozess unterziehen, mit ungewissem Ausgang des Asylverfahrens. Die Kapazität des Fachpersonals öffentlicher Dienstleistungen ist aufgrund fehlender Arbeitskräfte und Finanzmittel unzureichend, bei gleichzeitiger Zunahme der Einweisungen und der Notfälle mit psychiatrischen Problemen. Es gibt kaum systematische Untersuchungen des Substanzgebrauchs unter Flüchtlingen in Griechenland, Erfahrungen und Informationen sind limitiert. Qualitative und empirische Daten mehrerer Träger sprechen aber für eine Zunahme des Phänomens. Es wird das Profil von jungen, untätigen, armen Männer beschrieben, gut informiert über die verfügbaren Drogenszenen, viele schon in ihrer Heimat Gebraucher, mit Alkohol, Cannabis und Opioiden als Hauptsubstanzen. Alle offiziellen Drogenhilfeträger, Präventionszentren und viele Nichtregierungsorganisationen versuchen gemeinsam ein Netzwerk zu errichten, welches auf psychosoziale Unterstützung, reibungslose Integration von Kindern und Jugendlichen und Früherkennung von Gebrauchern abzielt. Es müssen aber noch alle Drogengebraucher an den Empfangszentren registriert, ein interinstitutioneller Träger aufgebaut, psychiatrische Beurteilungs-und Behandlungsmöglichkeiten in den Empfangszentren implementiert und Überweisungen zu spezialisierten Trägern ermöglicht werden.
Expertentreffen COPD: Integriertes Patientenmanagement bei COPD
Authors: Jany B. , Bals R. , Buhr-Schinner H. , Dreher M. , Koczulla R. , Jany L. , Meyer A. , Randerath W. , Steinkamp G.
Published: June 2018

Die Lebensqualität und Prognose der COPD-Patienten lässt trotz erheblich verbesserter medikamentöser Therapieoptionen weiterhin zu wünschen übrig. Ziel des Workshops war es, COPD-spezifische Hindernisse auf dem Weg zur verbesserten Betreuung der Patienten zu beschreiben. Dazu zählen der Sozial- und Bildungsstatus der COPD-Patienten sowie die gesellschaftliche Stigmatisierung der Erkrankung als selbstverschuldete „Raucherkrankheit“. Die strenge sektorale Trennung trägt zu Defiziten in der Betreuung bei. Im zweiten Teil des Workshops wurden Möglichkeiten der Verbesserung dargestellt. Die Nutzung IT-basierter Hilfsmittel, verbesserte Kommunikation zwischen Patienten und Therapeuten und zwischen den Sektoren des Gesundheitswesens, verbesserte Integration von Rehabilitation sowie durch Strategien des Selbstmanagements, sind solche Möglichkeiten. Als Schlussfolgerung konnte festgehalten werden, dass ein integriertes Patientenmanagement mit Einbeziehung multiprofessioneller Teams die Betreuungsqualität nachhaltig verbessern könnte.
NSAID und langkettige maritime ω-3-Fettsäuren
Authors: Gröber Uwe
Published: June 2018

Bei der rheumatoiden Arthritis greifen langkettige maritime ω-3-Fettsäuren auf mehreren Wegen in das Entzündungsgeschehen ein. Die regelmäßige Einnahme von EPA und DHA senkt den Bedarf an nichtsteroidalen Antirheumatika und die Nebenwirkungsrate.
Familiäre Kardiomyopathien – von der Phänomenologie zur zielgerichteten Therapie
Authors: Amr Ali , Katus Hugo , Meder Benjamin
Published: June 2018

Kardiomyopathien stellen eine heterogene Gruppe von Herzmuskelerkrankungen dar, die häufig durch genetische Mechanismen bedingt sind oder in ihrem Verlauf durch solche beeinflusst werden. Im Bereich der genetischen Diagnostik spielen insbesondere die monogenen und syndromalen Formen eine wichtige Rolle, da durch die Identifikation einer pathogenen genetischen Variante nicht nur eine Bestätigung der Diagnose, sondern auch eine Abklärung auf Anlageträgerschaft und damit Erkrankungsrisiko bei Angehörigen möglich ist, sowie in bestimmten Fällen eine Vorhersage des zu erwartenden Krankheitsverlaufs erfolgen kann. Schon heute ergeben sich durch Nachweis von bestimmten Genvarianten therapeutische Konsequenzen, was durch die zunehmende Anzahl an molekularen Therapieentwicklungen in Zukunft deutlich zunehmen wird. Die genetische Diagnostik von Patienten und Angehörigen ist dabei eingebettet in ein strukturiertes Kardiomyopathie-Management und folgt 3 Hauptkonzepten: 1) Identifizierung und, falls möglich, Behandlung der Krankheitsursache, 2) Erkennung und Verringerung des Risikos für den plötzlichen Herztod und 3) Prävention oder Behandlung von Herzinsuffizienz und deren Folgen. In dem vorliegenden Übersichtsartikel sollen aktuelle Entwicklungen zu den überwiegend genetischen, strukturellen Kardiomyopathien reflektiert werden.
High Serum Fractalkine is Associated with Lower Trabecular Bone Score in Premenopausal Women with Graves’ Disease
Authors: Kužma Martin , Vaňuga Peter , Binkley Neil , Ságová Ivana , Pávai Dušan , Blažíček Pavel , Kužmová Zuzana , Jackuliak Peter , Vaňuga Anton , Killinger Zdenko , Payer Juraj
Published: June 2018

Chemokine CX3CL1 (fractalkine) may be an important factor linking thyroid status and bone remodeling, through tetrac, a derivative of thyroxine. This study explores the relationship between serum fractalkine levels and parameters of thyroid status and bone in premenopausal women with Graves’ disease (GD) in comparison to healthy controls. This cross-sectional study included three premenopausal female groups: active GD; cured GD, and healthy age-, gender-, and BMI-matched controls. Measurement of serum fractalkine levels (Quantikine® ELISA), total amino-terminal peptide of procollagen type 1 (P1NP), CTx, thyroid hormones, BMD and trabecular bone score (TBS) were performed in all study subjects. Sixty women (21, 16, and 23 in active GD, cured GD, and healthy control groups, respectively) were included. Serum fractalkine levels were higher (p<0.05) in active and cured GD subjects compared to healthy controls (mean 0.7±0.14; 0.93±0.15, and 0.48±0.13 ng/ml, respectively). Lumbar spine BMD was lowest in the cured GD group in comparison to active GD and control group subjects (0.926±0.03; 1.016±0.03; 1.051±0.03 g/cm2; p<0.05, respectively). TBS was lower (p<0.05) in both GD groups than controls being lowest in those with active GD (1.395±0.02; 1.402±0.02, 1.469±0.02, respectively). Serum fractalkine concentration was positively correlated with fT4, and negatively correlated with TBS values. GD in pre-menopausal females is associated with increased serum fractalkine concentration and decreased TBS. Fractalkine may be a currently unappreciated link between hyperthyroidism and bone; further research into this possibility is needed.
ω-3-Fettsäuren bei Migräne
Authors: Schmiedel Volker
Published: June 2018

Ein 50-jähriger Migränepatient konnte durch regelmäßige Einnahme von Fischöl von seinen Beschwerden befreit werden. Die Therapie sollte sich am AA / EPA-Quotienten des Patienten orientieren und bei der Dosierung sind die unterschiedlichen DHA- und EPA-Gehalte der Öle bzw. Kapseln zu beachten.
Fusarihexins A and B: Novel Cyclic Hexadepsipeptides from the Mangrove Endophytic Fungus Fusarium sp. R5 with Antifungal Activities
Authors: Zhu Xinwei , Zhong Yu , Xie Zihui , Wu Manlin , Hu Zhibo , Ding Weijia , Li Chunyuan
Published: June 2018

Two novel cyclic hexadepsipeptides, fusarihexin A (1) and fusarihexin B (2), and two known compounds, cyclo-(L-Leu–L-Leu–D-Leu–L-Leu–L-Val) (3) and cyclo-(L-Leu–L-Leu–D-Leu–L-Leu–L-Ile) (4), were isolated from the marine mangrove endophytic fungus Fusarium sp. R5. Their chemical structures were elucidated on the basis of spectroscopic data and Marfeyʼs analysis. In an in vitro bioassay, fusarihexin A (1) remarkably inhibited three plant pathogenic fungi: Colletotrichum gloeosporioides (Penz.) Sacc., which causes anthracnose in many fruits and vegetables, Colletotrichum musae (Berk. and M. A. Curtis) Arx, which causes crown rot and anthracnose in bananas, and Fusarium oxysporum Schlecht. f. sp. lycopersici (Sacc.) W. C. Snyder et H. N. Hansen, which causes Fusarium wilt and fruit rot in tomatoes. Fusarihexin B (2) strongly inhibited C. gloeosporioides and C. musae. The compounds were more potent than carbendazim, which is widely used as an agricultural and horticultural fungicide worldwide.
Rhodium-Catalyzed Annulation of 2-Arylimidazoles and α-Aroyl Sulfoxonium Ylides toward 5-Arylimidazo[2,1-a]isoquinolines
Authors: Cheng Jiang , Yang Rui , Wu Xiaopeng , Sun Song , Yu Jin-Tao
Published: June 2018

A Rh-catalyzed annulation between 2-aryl-1H-benzo[d]imidazoles and α-aroyl sulfoxonium ylides was developed, affording a series of benzimidazo[2,1-a]isoquinolines in moderate to excellent yields. This procedure proceeded with the sequential ortho-C–H functionalization and cyclization, representing a facile and straightforward pathway to access such frameworks.
A Convergent Total Synthesis of the Biologically Active Benzo­furans Ailanthoidol, Egonol and Homoegonol from Biomass-Derived­ Eugenol
Authors: Camacho-Dávila Alejandro , Espinoza-Hicks José , Zaragoza-Galán Gerardo , Chávez-Flores David , Ramos-Sánchez Víctor , Tamariz Joaquín
Published: June 2018

An efficient, general synthetic protocol for the synthesis of the biologically active benzofurans ailanthoidol, egonol and homoegonol was developed. The key starting material, eugenol, is a naturally occurring and abundant precursor. The protocol, involving sequential acylation and intramolecular Wittig reaction, provides a convenient method for building the benzofuran moiety in good yield.
On the Mechanism of Thrombolytic Action of Thromboxane Synthetase Inhibitors
Authors: Korbut R , Dembińska-Kieć A , Świȩs J , Źmuda A , Gryglewski R J
Published: June 2018

Using our in vivo model for studying drugs which prevent deposition of thrombi or dissipate thrombi formed in extracorporeal circulation over a collagen strip superfused with arterial blood of anaesthetized and heparinized cats, we have found that dazoxiben - a thromboxane synthetase inhibitor - possesses not only antithrombotic but also thrombolytic potency in vivo (ED50 = 3.8 mg/kg i.v.). The thrombolytic potency of dazoxiben was antagonized by aspirin at a dose of 50 mg/kg i.v. Moreover, dazoxiben stimulated the generation of prostacyclin in isolated rat aortic slices incubated in platelet rich plasma, but not in platelet poor plasma. It is suggested that the thrombolytic potency of thromboxane synthetase inhibitors after their systemic administration is associated with the release of prostacyclin and/or prostacyclin-stable metabolites by the vascular endothelium owing to feeding of prostacyclin synthetase with prostaglandin endoperoxides acumulated in platelets following the inhibition of thromboxane synthetase.
Contact Thermography, 99mTc-Plasmin Scintimetry and 99mTc-Plasmin Scintigraphy as Screening Methods for Deep Venous Thrombosis Following Major Hip Surgery
Authors: Christensen S Winter , Wille-Jørgensen P , Kjær L , Stadeager C , Widding A , Vestergaard Aa , Bjerg-Nielsen A
Published: June 2018

Fifty-six patients scheduled for total hip alloplasty were screened for deep venous thrombosis by means of 99mTc-plasmin scintimetry, 99mTc-plasmin scintigraphy and contact thermography. Investigations were performed on the seventh postoperative day, and a total of 112 legs were examined. Bilateral ascending phlebography was used as reference procedure, and the criteria for deep venous thrombosis were intraluminal filling defects at phlebography. Six patients developed unilateral deep venous thrombosis. All three screening procedures revealed many false positive and several false negative results. The nosographic sensitivity/specificity was 33%/75% for scintimetry, 50%/91% for scintigraphy and 33%/87% for contact thermography, respectively. It is concluded that all three tests are of no value as screening methods for deep venous thrombosis following major elective hip surgery.
Release Pattern of the Vascular Plasminogen Activator and Its Inbibitor in Human Postvenous Occlusion Plasma as Assessed by a Spectrophotometric Solid-Phase Fibrin-tPA Activity Assay
Authors: Anglés-Cano E , Boutière B , Arnoux D , Masson C , Contant G , Benchimol P , Sampol J
Published: June 2018

Vascular or tissue-type plasminogen activatbr(plasma t-PA) is the circulating physiological fibrinolytic enzyme of endothelial cell origin which function is regulated by fibrin and a specific inhibitor (PAI). To study the pattern of release of t-PA and the behavior of t-PA-PAI complexes in plasma. we determined t-PA activity in 44 healthy subjects before and after 10 min offorearm venous occlusion using a new spectrophotmnetrio solid-phase fibrin-tPA activity assay. The assay is based on 1) the high affinity binding of t-PA tofibrin, and 2) the detection of fibrin-bound t-PA by measuring the release of pNA from a chromogenic substrate in the presence of plasminogeu. Values at.rest were rather undetectable in plasma (0.05 ± 0.03 IU/ml, in 23 out of 44 samples) but were positively detected in all the euglobulins: 0.88 ± 0.68 IU/ml. After venous occlusion the majority ofplasmas (36 out of 44) shoWed a slight increase in t-PA activity (0.65 ± 0.63 IU/ml) as compared to the important level observed in all the euglobulins (9.78 ± 9.58 IU/ml). So, the ratio plasma/euglobulin t-PA activity was very low (0.06) and remained identical in both pre- and postocclusion samples. However, when diluted plasmas were tested the inhibitory effect disappeared and t-PA activity increased indicating that although t-PA circulates in a neutralized state it can be available for fibrinolysis. Since 1) no binding of α2 antiplasmin to fibrin in solid-phase could be demonstrated, 2) there was no correlation between α2 antiplasmin and t-PA activity, and 3) a PAI-depleted plasma with a normal content of α2 antiplasmin did not suppress the activity of t-PA, the inhibitory effect was attributed to PAL Our findings suggest that both t-PA and PAI are released. by venous occlusion and circulates in plasma as a t-PA-PAI complex.
Plasma Thrombospondin as an Indicator of Intravascular Platelet Activation in Patients with Vasculitis
Authors: McCrohan M B , Huang S W , Sleasman J W , Klein P A , Kao K J
Published: June 2018

The use of plasma thrombospondin (TSP) concentration was investigated as an indicator of intravascular platelet activation. Patients (n = 20) with diseases that have known vasculitis were included in the study. The range and the mean of plasma TSP concentrations of patients with vasculitis were 117 ng/ml to 6500 ng/ml and 791±1412 ng/ml (mean ± SD); the range and the mean of plasma TSP concentrations of control individuals (n = 33) were 13 ng/ml to 137 ng/ml and 59±29 ng/ml. When plasma TSP concentrations were correlated with plasma concentrations of another platelet activation marker, β-thromboglobulin (P-TG), it was found that the TSP concentration inei eased exponentially as the plasma β-TG level rose. A positive correlation between plasma levels of plasma TSP and serum fibrin degradation products was also observed. The results suggest that platelets are the primary source of plasma TSP in patients with various vasculitis and that plasma TSP can be a better indicator than β-TG to assess intravascular platelet activation due to its longer circulation half life.
Plasminogen Activator Inhibitor-1 Is the Primary Inhibitor of Tissue-Type Plasminogen Activator in Pregnancy Plasma
Authors: Jørgensen Maja , Philips Malou , Thorsen Sixtus , Selmer Johan , Zeuthen Jesper
Published: June 2018

The aim of the present work was to clarify to what extent plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) contribute to the increase in plasma inhibition of tissue-type plasminogen activator (t-PA) observed during pregnancy. It was demonstrated that a monoclonal antibody against PAI-1 almost completely quenched inhibition of single-chain t-PA and most of the inhibition of two-chain t-PA in plasma during the third trimester of piegnancy. The remaining inhibition of two-chain t-PA was to a great extent abolished by a PAI-2 antibody. The second order rate constant (k1) for inhibition of single-chain t-PA by the inhibitor neutralized by the PAI-1 antibody was about 4.8 · 106 M-1 · s-1. The conversion of singlechain t-PA to the two-ehain form increased the reaction rate with the inhibitor about 3-fold. These kinetic data are compaiable with those obtained with TAI-l in non-pregnancy plasma oi with purified PAI-1. From the above results it is concluded that PAI-1 is the primary inhibitor of both single-chain and two chain t PA and that PAI-2 is the secondary inhibitor of two-chain t-PA in pregnancy plasma. The concentration of reactive PAI-1 versus gestation age was assayed in plasma from 6 women by binding of PAI-1 to 125I-labelled single-chain t-PA followed by quantitation of the labelled t-PA-PAI-1 complex after separation by SDS- polyacrylamide gel electrophoresis. It was found that the concentration of PAI-1 increased 4 to 8-fold during the gestation period reaching a level of about 1.4 nM at term. Post partum the plasma concentration declined abruptly within 24 h to the level observed in age-matched non-pregnant women.
Comparison of Specific Antibody, D-Phe-Pro-Arg-CH2Cl and Aprotinin for Prevention of In Vitro Effects of Recombinant Tissue-Type Plasminogen Activator on Haemostasis Parameters
Authors: Seifried E , Tanswell P
Published: June 2018

In vitro, concentration-dependent effects of rt-PA on a range of coagulation and fibrinolytic assays in thawed plasma samples were investigated. In absence of a fibrinolytic inhibitor, 2 μg rt-PA/ml blood (3.4 μg/ml plasma) caused prolongation of clotting time assays and decreases of plasminogen (to 44% of the control value), fibrinogen (to 27%), α2-antiplasmin (to 5%), FV (to 67%), FVIII (to 41%) and FXIII (to 16%).

Of three inhibitors tested, a specific polyclonal anti-rt-PA antibody prevented interferences in all fibrinolytic and most clotting assays. D-Phe-Pro-Arg-CH2Cl (PPACK) enabled correct assays of fibrinogen and fibrinolytic parameters but interfered with coagulometric assays dependent on endogenous thrombin generation. Aprotinin was suitable only for a restricted range of both assay types.

Most in vitro effects were observed only with rt-PA plasma concentrations in excess of therapeutic values. Nevertheless it is concluded that for clinical application, collection of blood samples on either specific antibody or PPACK is essential for a correct assessment of in vivo effects of rt-PA on the haemostatic system in patients undergoing fibrinolytic therapy.
Synergistic Effect on Thrombolysis of Sequential Infusion of Tissue-Type Plasminogen Activator (t-PA) Single-Chain Urokinase-Type Plasminogen Activator (scu-PA) and Urokinase in the Rabbit Jugular Vein Thrombosis Model
Authors: Collen D , Stassen J M , De Cock F
Published: June 2018

In a quantitative model of thrombolysis, consisting of rabbits with a 125T-fibrin labeled blood clot in the jugular vein, simultaneous intravenous infusion over 4 hours of t-PA and scu-PA or of t-PA and urokinase had a significantly greater (p <0.01) thrombolytic effect than could be anticipated on the basis of the added effects of each agent alone. In order to further investigate the mechanism of this in vivo synergism, recombinant t-PA (rt-PA) and scu-PA in synergistic amounts were infused: 1) simultaneously over 4 hours, 2) rt-PA over 1 hour, then 15 min later scu-PA over 2 hours and 3) scu-PA over 1 hour, then 15 min later rt-PA over 2 hours. Simultaneous infusion of 0.1 mg/kg rt-PA and 0.2 mg/kg scu-PA gave 48°2 percent thrombolysis (mean ° SEM, n = 5) and of 0.2 mg/kg rt-PA and 0.4 mg/kg scu-PA 67°5 percent (n = 5). When these infusions were given sequentially, rt-PA followed by scu-PA gave 32 °5 (n = 4) and 49 °8 (n = 4) percent lysis, but scu-PA followed by rt-PA yielded only 14° 1 (n = 4) and 21 ° 1 (n = 4) percent lysis, indicating that synergism occurs when rt-PA is followed by scu-PA but not when scu-PA is followed by rt-PA. In order to investigate the hypothesis that rt-PA predigests the clot resulting in more efficient plasminogen activation by scu-PA at the clot surface, partial thrombolysis was induced by injection of urokinase. Subsequent infusion of 0.4 mg/ kg of scu-PA did however not result in more thrombolysis than expected for additive effects. Infusion of 0.5 mg/kg of urokinase followed by 0.1 mg/kg rt-PA was not synergistic (24 °3 percent lysis, n = 3) whereas lysis by rt-PA followed by urokinase was 34°3 percent (p <0.1, n = 3).

Sequential therapy with rt-PA followed by scu-PA might constitute an alternative to simultaneous infusion of synergistic thrombolytic agents.
Potentiation by Heparin Fragments of Thrombolysis Induced with Human Tissue-Type Plasminogen Activator or Human Single-Chain Urokinase-Type Plasminogen Activator
Authors: Stassen J M , Juhan-Vague I , Alessi M C , De Cock F , Collen D
Published: June 2018

The effect of heparin and of two low molecular weight (low M
r) fractions of heparin on thrombolysis with recombinant human tissue-type plasminogen activator (rt-PA, Genentech Inc., So. San Francisco, CA) or human single chain urokinase-type plasminogen activator (scu-PA, Sandoz AG, Basle, Switzerland) was measured in a rabbit jugular vein thrombosis model. Four bolus injections of 200 anti-Factor Xa units/kg body weight of heparin (Liquemine, Hoffmann-La Roche, Basle, Switzerland), of 90 units/kg of CY 216 (Choay, Paris, France) or of 90 units/kg of CY 222 (Choay, Paris, France) were given intravenously, immediately after the start of the infusion of rt-PA or scu-PA and at hourly intervals during their intravenous infusion over 4 hours. The bolus injections resulted in anti-Factor Xa levels in plasma of 5.7 ± 1.2 units/ml just before the repeat bolus injections of heparin with corresponding values of 3.9 ± 0.2 units/ml for CY 216 and 1.6 ± 0.2 units/ml for CY 222.

Thrombolysis with 0.25 mg/kg rt-PA was 36 ± 1 percent (n = 9) in the absence of anticoagulant, 40 ± 1 percent (n = 7, p <0.05) in the presence of heparin, 49 ± 5 percent (n = 7, p <0.02) with CY 216 and 62 ± 5 percent (n = 7, p <0.01) with CY 222. Thrombolysis with 0.5 mg/kg scu-PA was 23 ± 1 percent (n = 4) without heparin, and increased to 24 ± 1 percent (n = 4, p >0.1) with heparin, to 32 ± 2 percent (n = 4, p <0.01) with CY 216 and to 33 ± 3 percent (n = 4, p <0.01) with CY 222.

It is concluded that, at these high doses, the two low M
r heparin fractions CY 216 and CY 222, potentiate thrombolysis by rt-PA and scu-PA in this animal model.
Plasma and Urinary Heparin Cofactor II Levels in Patients with Nephrotic Syndrome
Authors: Grau E , Oliver A , Félez J , Barceló P , Fernandez C , Ballarin J A , Fontcuberta J , Rutilant M L I
Published: June 2018

Heparin cofactor II (HC II) levels were measured by electroimmunoassay in plasmas and urines from 68 patients with nephrotic syndrome. In addition, antithrombin III (AT III) and protein C (PC) activities and antigens were measured also in the same group of patients. Seven of these patients had histories of thrombosis. Plasma HC II levels (mean ± SD 105 ± 43) were not different from levels in healthy subjects (94 ± 17). Only 5 patients had low plasma levels of HC II. None of the patients with thrombosis had low HC II levels. Even though measurable amounts of HC II were found in 25 urines from 50 patients. There was a relationship in the urinary excretion between HC II and AT III and their urinary clearances were quite similar. However, no correlation was found between plasma HC II and AT III levels, and levels of AT III activity and antigen were significantly lower than in healthy subjects. Three patients with hystories of thrombosis had low AT III levels. Most patients (including those with thrombosis histories) had high plasma PC levels and increased urinary loss.

It is suggested that HC II does not play an important role in the pathogenesis of thrombosis in nephrotic syndrome.