Resistance profiles of Neisseria gonorrhoeae isolates in Vienna, Austria: a phenotypic and genetic characterization from 2013 to 2020.

Objectives: International surveillance data show a constant rise in the number of Neisseria gonorrhoeae infections and an increase in drug resistance of N. gonorrhoeae. As recent N.

Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin.

Background And Objective: In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid.

Methods: Healthy subjects received a single intravenous bolus injection of a microdose of [C]ciprofloxacin (1.

Technology forecast: advanced therapies in late clinical research, EMA approval or clinical application via hospital exemption.

: The umbrella term ATMPs (Advanced Therapy Medicinal Products) comprises cell therapies, gene therapeutics and tissue engineered products. After implementation of the Regulation 1394/2007, only a couple of products have obtained a centralized European marketing authorisation. : The aim of the presented study is to give an overview on ATMPs available within the European Union either via centralized marketing authorisation or via national Hospital exemption.

Boron-Based Inhibitors of the NLRP3 Inflammasome.

NLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca homeostasis.

Lysophosphatidylcholine activates caspase-1 in microglia via a novel pathway involving two inflammasomes.

Inflammasomes regulate microglial caspase-1 activation and subsequent neuroinflammatory processes in brain pathology. In the present study, we have identified inflammasomes causing caspase-1 activation following stimulation of microglia with lysophosphatidylcholine (LPC), a proinflammatory lipid generated under pathological conditions in the brain. LPC-induced caspase-1 activation in microglia was found to depend on LPS prestimulation, inflammasome NLRP3 and adaptor molecule ASC.

Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized Phase 1 trial (MARSYAS I).

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial.

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production.

Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP.

Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes.

KCa 3.1-a microglial target ready for drug repurposing?

Over the past decade, glial cells have attracted attention for harboring unexploited targets for drug discovery. Several glial targets have attracted de novo drug discovery programs, as highlighted in this GLIA Special Issue. Drug repurposing, which has the objective of utilizing existing drugs as well as abandoned, failed, or not yet pursued clinical development candidates for new indications, might provide a faster opportunity to bring drugs for glial targets to patients with unmet needs.

Microglial Kv1.3 Channels and P2Y12 Receptors Differentially Regulate Cytokine and Chemokine Release from Brain Slices of Young Adult and Aged Mice.

Brain tissue damage following stroke or traumatic brain injury is accompanied by neuroinflammatory processes, while microglia play a central role in causing and regulating neuroinflammation via production of proinflammatory substances, including cytokines and chemokines. Here, we used brain slices, an established in situ brain injury model, from young adult and aged mice to investigate cytokine and chemokine production with particular focus on the role of microglia. Twenty four hours after slice preparation, higher concentrations of proinflammatory cytokines, i.

Does intrawound application of vancomycin influence bone healing in spinal surgery?

Purpose: Surgical site infections represent a major complication of spinal surgery. The application of lyophilised vancomycin into the wound is reported to significantly decrease infection rates. As concentrations applied locally can exceed the minimal bacterial inhibitory concentration for more than a 1000-fold, toxic side effects on local tissue may be possible.

Microglial K(+) channel expression in young adult and aged mice.

The K(+) channel expression pattern of microglia strongly depends on the cells' microenvironment and has been recognized as a sensitive marker of the cells' functional state. While numerous studies have been performed on microglia in vitro, our knowledge about microglial K(+) channels and their regulation in vivo is limited. Here, we have investigated K(+) currents of microglia in striatum, neocortex and entorhinal cortex of young adult and aged mice.

TRPM7 regulates proliferation and polarisation of macrophages.

Ion channels play pivotal roles in regulating important functions of macrophages, such as cytokine and chemokine production, migration, proliferation, phagocytosis and others. In this study, we have identified the transient receptor potential cation channel, subfamily M, member 7 (TRPM7) for the first time in macrophages. TRPM7 activity is differentially regulated in macrophages, i.

Patch clamp protocols to study ion channel activity in microglia.

Microglia express a variety of ion channels, which can be distinguished based on their ion selectivity into K(+), H(+), Na(+), Ca(2+), nonselective cation, and Cl(-) channels. With respect to their activation mode, voltage-, Ca(2+)-, calcium release-, G protein-, swelling-, and stretch-activated ion channels have been described in microglia. The best method to study the activity of microglial ion channels is the patch clamp technique.

Fluorescence imaging of intracellular Ca2+, Na+, and H+ in cultured microglia.

The behavior of microglial cells involves the activity of a variety of ion channels and ion transporters, which are implicated in the regulation of ion concentrations, membrane potential, and cell volume of microglia. Fluorescence imaging has been proven to be an elegant method to study ion concentration changes in intact microglial cells under physiological and pathophysiological conditions. The development of highly specific ion indicators has made it possible to detect changes in intracellular Ca(2+), Na(+), and H(+) concentrations of microglial cells as a result of ion channel or ion transporter activity.

Influence of intradiscal medication on nucleus pulposus cells.

Background Context: Eugene Carragee was the first to prove that provocative discography may contribute to intervertebral disc degeneration. Disc degeneration can be induced either by mechanical trauma caused by the puncturing needle or as a pharmacological effect of the drugs instilled into the disc.

Purpose: The aim of this study was to test the influence of cortisone, lidocaine, and iopamidol on nucleus pulposus cells under an in vitro setting.

Autografts for spinal fusion: osteogenic potential of laminectomy bone chips and bone shavings collected via high speed drill.

In case of revision or minimal invasive spinal surgery, the amount of autograft possibly harvested from the lamina and the spinous processes is limited. Ekanayake and Shad (Acta Neurochir 152:651-653, 2010) suggest the application of bone shavings harvested via high speed burr additionally or instead, but so far no data regarding their osteogenic potential exist. Aim of the study was to compare the osteogenic potential of bone chips and high speed burr shavings, and to evaluate the applicability of bone shavings as an autograft for spinal fusion.

Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia.

Production of reactive oxygen species (ROS) by microglial cells and subsequent oxidative stress are strongly implicated in the pathogenesis of Alzheimer's disease. Although it is recognized that amyloid-β (Aβ) plays a major role in inducing and regulating microglial ROS production in Alzheimer's disease, to date little is known about cellular mechanisms underlying Aβ-stimulated ROS production. Here, we identified ion channels involved in Aβ-induced microglial ROS production and in Aβ-induced microglial priming.

Implant survival analysis and failure modes of the X-Stop interspinous distraction device.

Study Design: Retrospective cohort study.

Objective: To review the clinical outcome, implant survivorship and reasons for failure after X-Stop implantation.

Summary Of Background Data: Conflicting data exist concerning clinical outcome of the X-Stop interspinous spacer and little information is being published about implant survivorship and the need for revision surgery.

Importance of lipid rafts for lysophosphatidylcholine-induced caspase-1 activation and reactive oxygen species generation.

Lipid rafts play an important role in regulating cellular processes and functions. Here, we demonstrate that in microglia stimulated with the pro-inflammatory lipid lysophosphatidylcholine (LPC), caspase-1 activation and NADPH oxidase activity depend on intact lipid rafts. Disruption of lipid rafts with methyl-β-cyclodextrin, fumonisin B1 or nystatin prevented LPC-stimulated caspase-1 activation and reactive oxygen species (ROS) production, whereas LPC-induced Na(+) influx remained unaffected.

Sodium dependence of lysophosphatidylcholine-induced caspase-1 activity and reactive oxygen species generation.

The proinflammatory cytokines interleukin (IL)-1β and IL-18 play pivotal roles in neuroinflammatory diseases. Caspase-1-mediated proteolytic cleavage is required to convert the premature, biologically inactive cytokines to their biologically active forms capable of promoting tissue inflammation. Although caspases have been recognized as potential therapeutic targets in inflammatory diseases, mechanisms regulating caspase-1 activation are not fully understood.

Stimulus-dependent requirement of ion channels for microglial NADPH oxidase-mediated production of reactive oxygen species.

Reactive oxygen species (ROS) produced by activated microglial cells play a pivotal role in the pathogenesis of neuro-degenerative and neuro-inflammatory diseases. Here we demonstrate that the pro-inflammatory lipid lysophosphatidylcholine (LPC) is capable of inducing microglial ROS production, which is mediated by the activity of NADPH oxidase. Inhibition of TRPV1 non-selective cation channels abolished ROS production in LPC-stimulated microglia, whereas inhibitors of K(+) channels, H(+) channels and Cl(-) channels had no significant effects.

Ion channels in monocytes and microglia/brain macrophages: promising therapeutic targets for neurological diseases.

Monocyte recruitment and their subsequent transformation to brain macrophages as well as microglial activation are key events in a variety of severe neurological diseases. Activated microglia and brain macrophages can have detrimental effects in brain pathology via the promotion of inflammatory processes and the release of neurotoxic substances. Therefore, it is of great interest to develop strategies aiming at i) the reduction of monocyte infiltration into the damaged brain and ii) specific inhibition of neurotoxic effects by activated microglia / brain macrophages.

Importance of the non-selective cation channel TRPV1 for microglial reactive oxygen species generation.

Activated microglial cells generate reactive oxygen species (ROS), which have detrimental effects in neuroinflammatory and neurodegenerative diseases. In the present study, we have identified a novel mechanism involved in microglial NADPH oxidase-mediated ROS production. In PMA-stimulated microglia, ROS production was substantially reduced upon inhibition of the non-selective cation channel TRPV1 with La(3+), ruthenium red, capsazepine and 5-iodo-resinferatoxin.