Combined Cyclosporin A and Hypothermia Treatment Inhibits Activation of BV-2 Microglia but Induces an Inflammatory Response in an Ischemia/Reperfusion Hippocampal Slice Culture Model

Introduction: Hypothermia attenuates cerebral ischemia-induced neuronal cell death associated with neuroinflammation. The calcineurin inhibitor cyclosporin A (CsA) has been shown to be neuroprotective by minimizing activation of inflammatory pathways. Therefore, we investigated whether the combination of hypothermia and treatment with CsA has neuroprotective effects in an oxygen-glucose deprivation/reperfusion (OGD/R) injury model in neuronal and BV-2 microglia monocultures, as well as in an organotypic hippocampal slice culture (OHSC). Methods: Murine primary neurons, BV-2 microglia, and OHSC were pretreated with CsA and exposed to 1 h OGD (0.2% O2) followed by reperfusion at normothermia (37°C) or hypothermia (33.5°C). Cytotoxicity was measured by lactate dehydrogenase and glutamate releases. Damage-associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1), heat shock protein 70 (Hsp70), and cold-inducible RNA-binding protein (CIRBP) were detected in cultured supernatant by western blot analysis. Interleukin-6 (IL-6), Interleukin-1α and -1β (IL-1α/IL1-β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP1), inducible nitric oxide synthase (iNOS), glia activation factors ionized calcium-binding adapter molecule 1 (Iba1), and transforming growth factor β1 (TGF-β1) gene expressions were analyzed by RT-qPCR. Results: Exposure to OGD plus 10 μM CsA was sufficient to induce necrotic cell death and subsequent release of DAMPs in neurons but not BV-2 microglia. Moreover, OGD/R-induced secondary injury was also observed only in the neurons, which was not attenuated by cooling and no increased toxicity by CsA was observed. BV-2 microglia were not sensitive to OGD/R-induced injury but were susceptible to CsA-induced toxicity in a dose dependent manner, which was minimized by hypothermia. CsA attenuated IL-1β and Iba1 expressions in BV-2 microglia exposed to OGD/R. Hypothermia reduced IL-1β and iNOS expressions but induced TNF-α and Iba1 expressions in the microglia. However, these observations did not translate to the ex vivo OHCS model, as general high expressions of most cytokines investigated were observed. Conclusion: Treatment with CsA has neurotoxic effects on primary neurons exposed to OGD but could inhibit BV-2 microglia activation. However, CsA and hypothermia treatment after ischemia/reperfusion injury results in cytotoxic neuroinflammation in the complex ex vivo OHSC

Post-TTM Rebound Pyrexia after Ischemia-Reperfusion Injury Results in Sterile Inflammation and Apoptosis in Cardiomyocytes

Introduction. Fever is frequently observed after acute ischemic events and is associated with poor outcome and higher mortality. Targeted temperature management (TTM) is recommended for neuroprotection in comatose cardiac arrest survivors, but pyrexia after rewarming is proven to be detrimental in clinical trials. However, the cellular mechanisms and kinetics of post- TTM rebound pyrexia remain to be elucidated. Therefore, we investigated the effects of cooling and post-TTM pyrexia on the inflammatory response and apoptosis in a cardiomyocyte ischemia-reperfusion (IR) injury model. Methods. HL-1 cardiomyocytes were divided into the following groups to investigate the effect of oxygen-glucose deprivation/reperfusion (OGD/R), hypothermia (33.5°C), and pyrexia (40°C): normoxia controls maintained at 37°C and warmed to 40°C, OGD/R groups maintained at 37°C and cooled to 33.5°C for 24 h with rewarming to 37°C, and OGD/R pyrexia groups further warmed from 37 to 40°C. Caspase-3 and RBM3 were assessed by Western blot and TNF-α, IL-6, IL-1β, SOCS3, iNOS, and RBM3 transcriptions by RT-qPCR. Results. OGD-induced oxidative stress (iNOS) in cardiomyocytes was attenuated post-TTM by cooling. Cytokine transcriptions were suppressed by OGD, while reperfusion induced significant TNF-α transcription that was exacerbated by cooling. Significant inductions of TNF-α, IL-6, IL-1β, and SOCS3 were observed in noncooled, but not in cooled and rewarmed, OGD/R-injured cardiomyocytes. Further warming to pyrexia induced a sterile inflammatory response in OGD/R-injured groups that was attenuated by previous cooling, but no inflammation was observed in pyrexic normoxia groups. Moreover, cytoprotective RBM3 expression was induced by cooling but suppressed by pyrexia, correlating with apoptotic caspase-3 activation. Conclusion. Our findings show that maintaining a period of post-TTM “therapeutic normothermia” is effective in preventing secondary apoptosis-driven myocardial cell death, thus minimizing the infarct area and further release of mediators of the innate sterile inflammatory response after acute IR injury

BAT Algorithm Based Beamformer for Interference Suppression by Controlling the Complex Weight

In this study, an adaptive beamformer for pattern nulling of Uniformly Spaced Linear Array (ULA) antennas, which utilized BAT algorithm (BA) to suppress interferences, has been proposed. This pattern nulling has been obtained by controlling the complex weight (both the phase and the amplitude) of each array element. So as to verify the proposal, a number of scenarios of ULA pattern imposed the pre-set nulls have been carried out and compared with those of accelerated particle swarm optimization (APSO). The proposed beamformer has demonstrated the capability to place with precise single, multiple, and broad nulls at arbitrary interference directions, suppress side lobes, and maintain a predefined beamwidth. Moreover, the beamformer shows faster convergence and higher efficiency regarding null steering and side lobe suppression in pattern synthesis, as compared with an APSO based beamformer

Study on the Chemistry and Antimicrobial Activity of Psychotria reevesii Wall. (Rubiaceae)

The first chemical investigation on Vietnamese medicinal plant Psychotria reevesii Wall. (Rubiaceae) led to the isolation and structural determination of β-sitosterol and stigmasterol as a mixture, 1-octacosene, and asperglaucide from n-hexane- and CHCl3-soluble fractions of MeOH extract from the aerial parts of P. reevesii. Phytochemical screening based on color reactions, HPLC analysis, and NMR spectroscopy revealed the concentration of condensed tannins in EtOAc- and n-BuOH soluble fractions. The high accumulation of tannins may be responsible for the antibacterial activities of the polar fractions against Staphylococcus aureus, Pseudomonas aeruginosa, Shigella sonnei, and Shigella flexneri. However, they did not exhibit any inhibitory effect against Escherichia coli, Candida albicans, and Candida stellatoides.Keywords: Psychotria reevesii; Rubiaceae; asperglaucide; antibacterial activity; antifungal activity

Guide to Participatory Scenario Planning (PSP): Experiences from the Agro-Climate Information Services for women and ethnic minority farmers in South-East Asia (ACIS) project in Ha Tinh and Dien Bien province, Vietnam

The Participatory scenario planning (PSP) workshop is a valuable knowledge-sharing platform through which stakeholders, including those who support the implementation of PSP (i.e., meteorological and agricultural services) and those who access and use the climate information (i.e., technical experts, and farmers) meet to discuss adaptation actions within the context of climate information. The PSP approach was developed under CARE International’s Adaptation Learning Programme (ALP). It was then adapted to Vietnam, Laos, and Cambodia under the Agro-Climate Information Services for women and ethnic minority farmers in South-East Asia (ACIS) project by CARE International in Vietnam and World Agroforestry Centre (ICRAF) Vietnam

A fatty acid, flavonoids, and steroids from Zingiber penisulare. I. Theilade (zingiberaceae)

The first chemical study of Zingiber penisulare I. Theilade (Zingiberaceae) resulted in the isolation of a fatty acid, eicosanoic acid (1), three kaempferol derivatives, 5-hydroxy-3,4',7-trimethoxyflavone  (2), 4',5-dihydroxy-7-methoxyflavonol (5), and 4',5-dihydroxy-3,7-dimethoxyflavone (6), b-sitosterol (3), and 6b-hydroxystigmast-4-ene-3-one (4). Their chemical structures were determined by spectroscopic analyses. Keywords: Zingiber penisulare; Zingiberaceae; kaempferol; flavonol; stigmastane

The Effects of Targeted Temperature Management on Oxygen-Glucose Deprivation/Reperfusion-Induced Injury and DAMP Release in Murine Primary Cardiomyocytes

Introduction. Ischemia/Reperfusion (I/R) is a primary cause of myocardial injury after acute myocardial infarction resulting in the release of damage-associated molecular patterns (DAMPs), which can induce a sterile inflammatory response in the myocardial penumbra. Targeted temperature management (TTM) after I/R has been established for neuroprotection, but the cardioprotective effect remains to be elucidated. Therefore, we investigated the effect of TTM on cell viability, immune response, and DAMP release during oxygen-glucose deprivation/reperfusion (OGD/R) in murine primary cardiomyocytes. Methods. Primary cardiomyocytes from P1-3 mice were exposed to 2, 4, or 6 hours OGD (0.2% oxygen in medium without glucose and serum) followed by 6, 12, or 24 hours simulated reperfusion (21% oxygen in complete medium). TTM at 33.5°C was initiated intra-OGD, and a control group was maintained at 37°C normoxia. Necrosis was assessed by lactate dehydrogenase (LDH) release and apoptosis by caspase-3 activation. OGD-induced DAMP secretions were assessed by Western blotting. Inducible nitric oxide synthase (iNOS), cytokines, and antiapoptotic RBM3 and CIRBP gene expressions were measured by quantitative polymerase chain reaction. Results. Increasing duration of OGD resulted in a transition from apoptotic programmed cell death to necrosis, as observed by decreasing caspase-3 cleavage and increasing LDH release. DAMP release and iNOS expression correlated with increasing necrosis and were effectively attenuated by TTM initiated during OGD. Moreover, TTM induced expression of antiapoptotic RBM3 and CIRBP. Conclusion. TTM protects the myocardium by attenuating cardiomyocyte necrosis induced by OGD and caspase-3 activation, possibly via induction of antiapoptotic RBM3 and CIRBP expressions, during reperfusion. OGD induces increased Hsp70 and CIRBP releases, but HMGB-1 is the dominant mediator of inflammation secreted by cardiomyocytes after prolonged exposure. TTM has the potential to attenuate DAMP release

An Automated Mobile Game-based Screening Tool for Patients with Alcohol Dependence

Traditional methods for screening and diagnosis of alcohol dependence are typically administered by trained clinicians in medical settings and often rely on interview responses. These self-reports can be unintentionally or deliberately false, and misleading answers can, in turn, lead to inaccurate assessment and diagnosis. In this study, we examine the use of user-game interaction patterns on mobile games to develop an automated diagnostic and screening tool for alcohol-dependent patients. Our approach relies on the capture of interaction patterns during gameplay, while potential patients engage with popular mobile games on smartphones. The captured signals include gameplay performance, touch gestures, and device motion, with the intention of identifying patients with alcohol dependence. We evaluate the classification performance of various supervised learning algorithms on data collected from 40 patients and 40 age-matched healthy adults. The results show that patients with alcohol dependence can be automatically identified accurately using the ensemble of touch, device motion, and gameplay performance features on 3-minute samples (accuracy=0.95, sensitivity=0.95, and specificity=0.95). The present findings provide strong evidence suggesting the potential use of user-game interaction metrics on existing mobile games as discriminant features for developing an implicit measure to identify alcohol dependence conditions. In addition to supporting healthcare professionals in clinical decision-making, the game-based self-screening method could be used as a novel strategy to promote alcohol dependence screening, especially outside of clinical settings

Promising results of a clinical feasibility study: CIRBP as a potential biomarker in pediatric cardiac surgery

ObjectiveCold-inducible RNA binding Protein (CIRBP) has been shown to be a potent inflammatory mediator and could serve as a novel biomarker for inflammation. Systemic inflammatory response syndrome (SIRS) and capillary leak syndrome (CLS) are frequent complications after pediatric cardiac surgery increasing morbidity, therefore early diagnosis and therapy is crucial. As CIRBP serum levels have not been analyzed in a pediatric population, we conducted a clinical feasibility establishing a customized magnetic bead panel analyzing CIRBP in pediatric patients undergoing cardiac surgery.MethodsA prospective hypothesis generating observational clinical study was conducted at the German Heart Center Berlin during a period of 9 months starting in May 2020 (DRKS00020885, https://drks.de/search/de/trial/DRKS00020885). Serum samples were obtained before the cardiac operation, upon arrival at the pediatric intensive care unit, 6 and 24 h after the operation in patients up to 18 years of age with congenital heart disease (CHD). Customized multiplex magnetic bead-based immunoassay panels were developed to analyze CIRBP, Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Monocyte chemotactic protein 1 (MCP-1), Syndecan-1 (SDC-1), Thrombomodulin (TM), Vascular endothelial growth factor (VEGF-A), Angiopoietin-2 (Ang-2), and Fibroblast growth factor 23 (FGF-23) in 25 µl serum using the Luminex MagPix® system.Results19 patients representing a broad range of CHD (10 male patients, median age 2 years, 9 female patients, median age 3 years) were included in the feasibility study. CIRBP was detectable in the whole patient cohort. Relative to individual baseline values, CIRBP concentrations increased 6 h after operation and returned to baseline levels over time. IL-6, IL-8, IL-10, and MCP-1 concentrations were significantly increased after operation and except for MCP-1 concentrations stayed upregulated over time. SDC-1, TM, Ang-2, as well as FGF-23 concentrations were also significantly increased, whereas VEGF-A concentration was significantly decreased after surgery.DiscussionUsing customized magnetic bead panels, we were able to detect CIRBP in a minimal serum volume (25 µl) in all enrolled patients. To our knowledge this is the first clinical study to assess CIRBP serum concentrations in a pediatric population