Resveratrol Differentially Regulates NAMPT and SIRT1 in Hepatocarcinoma Cells and Primary Human Hepatocytes: Resveratrol Differentially Regulates NAMPT and SIRT1 inHepatocarcinoma Cells and Primary Human Hepatocytes

Resveratrol is reported to possess chemotherapeutic properties in several cancers. In this study, we wanted to investigate the molecular mechanisms of resveratrol-induced cell cycle arrest and apoptosis as well as the impact of resveratrol on NAMPT and SIRT1 protein function and asked whether there are differences in hepatocarcinoma cells (HepG2, Hep3B cells) and non-cancerous primary human hepatocytes. We found a lower basal NAMPT mRNA and protein expression in hepatocarcinoma cells compared to primary hepatocytes. In contrast, SIRT1 was significantly higher expressed in hepatocarcinoma cells than in primary hepatocytes. Resveratrol induced cell cycle arrest in the S- and G2/M- phase and apoptosis was mediated by activation of p53 and caspase-3 in HepG2 cells. In contrast to primary hepatocytes, resveratrol treated HepG2 cells showed a reduction of NAMPT enzymatic activity and increased p53 acetylation (K382). Resveratrol induced NAMPT release from HepG2 cells which was associated with increased NAMPT mRNA expression. This effect was absent in primary hepatocytes where resveratrol was shown to function as NAMPT and SIRT1 activator. SIRT1 inhibition by EX527 resembled resveratrol effects on HepG2 cells. Furthermore, a SIRT1 overexpression significantly decreased both p53 hyperacetylation and resveratrol-induced NAMPT release as well as S-phase arrest in HepG2 cells. We could show that NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and primary hepatocytes and that resveratrol did not act as a SIRT1 activator in hepatocarcinoma cells

Retinal thinning in phenylketonuria and Gaucher disease type 3

Purpose Retinal alterations in inherited metabolic diseases associated with neurodegeneration are poorly studied. The objective was to study retinal thickness, specifically the components of the ganglion cell complex (GCC)—nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)—using spectral-domain optical coherence tomography (SD-OCT) in two different diseases with potential dopaminergic depletion, phenylketonuria (PKU) and Gaucher disease type 3 (GD3). Methods Retinal layers in 19 patients with PKU, 15 patients with GD3, and 93 healthy individuals were measured using peripapillary ring scan and macular SD-OCT. Linear mixed models were computed including an adjustment for age, sex, and spherical equivalent. We calculated Spearman’s rank correlations between retinal layer measurements and clinical and/or laboratory parameters. Results Thinning of total retinal thickness was found in the macular inner ring (p = 0.002), and outer ring (p = 0.012), sparing the fovea (p = 0.12) in PKU, while in GD3, all subfields were thinned (fovea p < 0.001, inner ring p = 0.047, outer ring 0.07). In both conditions, thinning was most evident in the NFL, GCL, and IPL, while OPL (outer plexiform layer) was thickened. Peripapillary retinal nerve fiber layer measurements remained normal. GCL and IPL in PKU correlated with tyrosine serum concentration. Conclusion Thinning of the NFL, GCL, and IPL, with thickened OPL, are both found in PKU and in GD3. Low dopamine concentrations in the retina might promote these effects. However, these data do not give evidence that retinal measurements can be used as a biomarker for disease severity in patients with GD3

Integrierte Notfallzentren: eine Lösung zur Patientensteuerung? Eine literaturgestützte empirische Primärdatenerhebung

Hintergrund Die deutschen Notaufnahmen sind überfüllt. Immer mehr Patienten suchen im Bedarfsfall eine Notaufnahme auf, obwohl diese teilweise von einem niedergelassenen Arzt behandelt werden könnten. Durch die geplante Einführung von integrierten Notfallzentren (INZ) soll dieser Überfüllung und Überlastung der Notaufnahmen entgegengewirkt werden. Doch können INZ zur Patientensteuerung genutzt werden und welche personellen und strukturellen Voraussetzungen müssen dafür erfüllt sein? Methode Zur Beantwortung dieser Fragestellungen wurde eine literaturgestützte empirische Primärdatenerhebung durchgeführt. Eine systematische Literaturrecherche bildete dabei die Grundlage für eine weiterführende Querschnittserhebung. Ziel war es, publizierte Meinungen und Positionen verschiedener Fachverbände, Gesellschaften und Experten unter Klinikern zu hinterfragen. Die Datenerhebung fand durch eine quantitative Befragung in Form einer Online-Umfrage statt. Adressaten der Online-Umfrage waren alle ärztlichen und pflegerischen Notaufnahmeleitungen (N = 331) in Bayern. Zur Datenauswertung wurde das Statistikprogramm SPSS verwendet. Ergebnisse Ein Drittel der Notaufnahmeleitungen (N = 107) hat sich an der Online-Umfrage beteiligt. Die Teilnehmer setzen sich aus 57 ärztlichen und 50 pflegerischen Leitungen zusammen. Mehr als 80 % der befragten Teilnehmer erachten INZ als sinnvoll. Als wichtige Voraussetzungen für die Etablierung von INZ gelten dabei die Zusammenarbeit aller Beteiligten, eine validierte Ersteinschätzung, angemessene Personalbemessungsmodelle sowie eine transparente Ausgestaltung von INZ. Diskussion INZ werden momentan als ein vielversprechender Lösungsansatz betrachtet. Damit eine Patientensteuerung gelingen kann, müssen die genannten Voraussetzungen erfüllt sein.Background German emergency departments are overcrowded. More and more patients are visiting an emergency room, even though some of them could be treated by a general practitioner. The planned introduction of integrated emergency centers (IECs) is intended to counteract this overcrowding and congestion in emergency rooms. But can IECs be used for patient management and what personnel and structural requirements are needed for this? Methods This is a literature-supported empiric primary data assessment. Therefore, a systematic literature review is the base for the further cross-sectional review. The aim was to question published opinions and positions of different professional associations, societies and clinical experts. Data were collected through a quantitative online survey. The online survey was sent to all medical and nursing managers (N = 331) of emergency departments in Bavaria. Data were analyzed using the statistic program SPSS. Results One-third of emergency department managers (N = 107) responded to the online survey. Participants consisted of 57 medical and 50 nursing department managers. More than 80% of the surveyed participants consider IECs to be useful. Important prerequisites for the establishment of IECs include collaboration of all stakeholders, a validated initial assessment, appropriate staffing models and a transparent design of IECs. Conclusion IECs are currently considered as a promising solution. In order for patient management to succeed, the above conditions must be met

Corneal topometric, aberrometric and biomechanical parameters in mucopolysaccharidosis patients

AIMS: To report corneal topometric and aberrometric values in mucopolysaccharidosis (MPS) and to investigate their correlation with biomechanical corneal parameters. METHODS: One randomly chosen eye of 20 MPS patients with no to moderate corneal clouding and one eye of 23 healthy controls with comparable age were prospectively included into this study. Corneal surface regularity was assessed by index of surface variance (ISV), -vertical asymmetry (IVA), -height asymmetry (IHA), -height decentration (IHD); keratoconus index (KI), central keratoconus index (CKI) and Zernike indices of anterior and posterior corneal surface using Scheimpflug imaging (Pentacam). Corneal resistance factor (CRF) and corneal hysteresis (CH) were assessed by Ocular Response Analyzer. Statistical analyses were performed using Mann-Whitney-Test and Spearman Correlation Coefficients. RESULTS: IVA, ISV, IHD, IHA, but not KI and CKI were significantly higher in MPS patients compared to age matched healthy controls. Spherical aberration and asphericity coefficients either at the anterior or at the posterior corneal surface differed significantly between both groups. The grade of the MPS-associated corneal opacity correlated significantly with ISV (rho = 0.52), IVA (rho = 0.54), IHA (rho = 0.57) and IHD (rho = 0.48). Density of the MPS-affected corneas correlated significantly with ISV (rho = 0.52), IVA (rho = 0.72), IHA (rho = 0.57), IHD (rho = 0.69), 3rd order horizontal trefoil aberration at the posterior (rho = 0.62) and anterior surface (rho = 0.48) as well as with CH (rho = 0.55) and CRF (rho = 0.57). Spherical aberration at the back surface correlated with CRF and CH in MPS and in healthy controls. CONCLUSIONS: This is the first study analyzing shape of the corneal surface in MPS patients. Topometric indices of corneal asymmetry are significantly increased and correlate with MPS-related corneal opacity and density. Spherical aberration and asphericity coefficient at the front and at the back corneal surface differ significantly between MPS and healthy controls

Ethical and legal evaluation of drone defense projects in police work: The protection of fundamental rights in public security measures

Die zunehmende Nutzung von unbemannten Flugsystemen (Unmanned Aerial Vehicles [UAV] – nachfolgend: Drohnen) birgt neue Gefährdungspotenziale für die zivile Sicherheit. Eine Drohne kann von einem Hobbypiloten genutzt werden, um Luftaufnahmen zu machen, sie kann aber auch gefährliche Spreng- oder Giftstoffe transportieren. Nicht zuletzt können Drohnen eine Gefahr darstellen, indem sie (unbeabsichtigt) abstürzen oder (gezielt) zum Absturz gebracht werden. Als Antwort auf diese Bedrohungslagen reagieren öffentliche und private Einrichtungen mit der Entwicklung von Drohnenabwehrsystemen für den zivilen Bereich. Der Beitrag soll die Folgen des Einsatzes von Drohnenabwehrsystemen durch die Polizei aus ethischer und rechtlicher Perspektive bewerten. Im Vordergrund stehen dabei die Überwachungspotenziale des Systems und die Abwägung von Risiken der Drohnenabwehr in Hinsicht auf den verfassungsrechtlichen Grundrechtsschutz.The increasing use of unmanned aerial vehicles (UAVs/drones) encompasses new potential risks for civil security. While drones can be deployed by amateur pilots for aerial photography, they may also transport dangerous explosives or toxic material. The drone may pose a threat through crashing – either by accident or on purpose. Facing these security threats, public and private institutions react by promoting research and development of drone defense systems for the civil sector. This article aims to evaluate ethical and legal consequences of the application of drone defense systems by the German police. It focuses on the surveillance potential of such systems and the assessment of risks in relation to the protection of fundamental rights and civil liberties

Resveratrol differentially regulates NAMPT and SIRT1 in hepatocarcinoma cells and primary human hepatocytes

Resveratrol is reported to possess chemotherapeutic properties in several cancers. In this study, we wanted to investigate the molecular mechanisms of resveratrol-induced cell cycle arrest and apoptosis as well as the impact of resveratrol on NAMPT and SIRT1 protein function and asked whether there are differences in hepatocarcinoma cells (HepG2, Hep3B cells) and non-cancerous primary human hepatocytes. We found a lower basal NAMPT mRNA and protein expression in hepatocarcinoma cells compared to primary hepatocytes. In contrast, SIRT1 was significantly higher expressed in hepatocarcinoma cells than in primary hepatocytes. Resveratrol induced cell cycle arrest in the S- and G2/M- phase and apoptosis was mediated by activation of p53 and caspase-3 in HepG2 cells. In contrast to primary hepatocytes, resveratrol treated HepG2 cells showed a reduction of NAMPT enzymatic activity and increased p53 acetylation (K382). Resveratrol induced NAMPT release from HepG2 cells which was associated with increased NAMPT mRNA expression. This effect was absent in primary hepatocytes where resveratrol was shown to function as NAMPT and SIRT1 activator. SIRT1 inhibition by EX527 resembled resveratrol effects on HepG2 cells. Furthermore, a SIRT1 overexpression significantly decreased both p53 hyperacetylation and resveratrol-induced NAMPT release as well as S-phase arrest in HepG2 cells. We could show that NAMPT and SIRT1 are differentially regulated by resveratrol in hepatocarcinoma cells and primary hepatocytes and that resveratrol did not act as a SIRT1 activator in hepatocarcinoma cells

Full length interleukin 33 aggravates radiation-induced skin reaction

The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction

Impact of cross-linking procedure on perioperative quality of life in keratoconus patients

Background: To evaluate the effect of crosslinking (CXL) with riboflavin for keratoconus (KC) therapy on quality of life (QoL): comparison of keratoconus patients with and without treatment. Methods: Prospective monocentric study. We recruited patients with progressive KC and with stable disease. Patients with progressive disease received cross-linking treatment; patients with stable disease were monitored. We compared QoL in both groups over 6 months and detected the influence of cross-linking treatment on QoL. QoL was assessed by NEI-VFQ-25, EQ-5D 5L, and EQ-Visual analog scale (VAS). In the evaluation of the Nei VFQ, the subgroups LFVFS and LFSES were calculated. Results: We enrolled 31 eyes of 31 patients in the intervention group and 37 eyes of 37 patients in the control group. Medians with standard deviations (SD) were calculated. All QoL-tests showed equal scores at baseline in both groups. At V2, one day after the treatment, EQ-VAS (56.4), LFVFS (57.4), and EQ5D5L (0.59) were significantly reduced. At V3 (one week after treatment), all results returned to baseline level. LFSES was not affected by the treatment. It remained stable (V2 85.4, V3 84.3). Comparing the baseline scores with the follow-up scores at month 6, we found a significant increase in QoL in all tests in the intervention group. Otherwise, the quality of life in the control group did not change over time. Conclusions: Cross-linking led only to a short-term reduction in QoL. Although the treatment is painful for a few days, no effect on general quality of life LVSES has been demonstrated. QoL already returned to baseline after one week and the patients were not limited anymore